From 1265 on Thomas was assigned to the Convent of Santa Sabina in Rome in order to found a general studium for the formation of the Brothers. Perhaps he took up again his commentary on the Sentences for the basic course in theology, but then he abandoned its methodology in order to offer his Brothers a theological synthesis of a wider scope.

This theological endeavor was innovative both with respect to what had been written before and to the schema of the same Sentences. It's the origin of his great project, the Summa theologiae, an organic synthesis of theology, which he wrote without giving it a title. It was written for theological students in the studium, a work that occupied him until his death. (It remained incomplete, ending at question 90, article 4 of the third part.) Subdivided into questions and articles, it made heavy use of philosophic, biblical and patristic texts. There are objections (arguments for and against a thesis) already tried in the Sentences. By1268 Thomas had written the Prima pars of the Summa. The Prima secondae would be written in Paris by 1270. He would only finish the Secunda secundae at the end of 1271. The Tertia pars, begun in Paris in 1271 or 1272, was continued in Naples until that fatal day of December 6, 1273, the day on which Thomas ceased from all intellectual activity. The so-called Supplement of the Summa was composed instead by his disciples on the basis of Thomas's commentary on the Sentences.

The structure of the Summa follows a complex plan. It is divided into three long parts: the first treats of God; the second, subdivided into two parts, treats of the movement of the creature to God; and the third considers Christ who, in his humanity, is the life which leads to God, the ultimate goal. The first part, in turn, is organized into three sections: the attributes which follow upon the essence of God (questions 2 – 26); that which concerns the distinction of the divine Persons (questions 27 - 43); and the way in which creatures proceed from God (questions 44 – 119). This last subsection is further divided: first, creation (questions 44 - 46); then, the distinction between creatures (questions 47-49), and they are the angels (questions 50 - 64), the Creator's work in the first six days (questions 65 -74), and man (questions 75 -102); and, lastly, the way in which God governs his creatures either directly or through the so-called secondary causes (questions 103 – 119).

The second part is made up of two large sections that consider the return of man to God, his ultimate end. The first section, called the Prima secundae, is a very long and detailed tract. Questions 1- 5 are given to the identification of the ultimate end, happiness. The next section takes up human acts (questions 6 – 89), which are the means by which man reaches the ultimate end (happiness). It examines free and voluntary human acts, that is their capacity to be good or bad (questions 6 – 21), and the soul's passions (questions 22 – 48). The internal habits that qualify the powers of the soul, that is the virtues and vices, come next (questions 49 – 89). Finally it speaks of the external principles which influence a human act: the law (questions 90 - 108); and grace (questions 109 – 114).

In the second section, the Secunda secundae, Thomas analyzes in depth the theological matter presented in the Prima secundae; that is, the theological virtues (questions 1 - 46), and the cardinal virtues (questions 47 - 170). He makes evident for each virtue its proper characteristics, and its contrary sins. Finally he presents the charisms and the states of life, the true wealth of the organism that is the Church (questions 171 – 189).

In the third part, the Tertia pars, christology is the methodological path that Thomas chose to lead his readers to a consideration of the results of the work completed by God in human history. What emerges is the strongest biblical and patristic foundation of his thought. Questions 1 – 59 study the mystery of Christ who gives salvation to men. In particular they treat of Christ in Himself and in the mystery if the Incarnation (questions 1 – 26), and Christ's accomplishments in the entire Paschal mystery (questions 27 – 59). These questions are a true and proper theology of the mystery of the life of Jesus.

The second section of the Tertia pars studies the sacraments which give men the experience of salvation in Christ. The sacraments in general are first considered (questions 60 - 65), and then each sacrament up to penance (questions 66– 90). It is at this point that Thomas's great theological project stops and remains incomplete because of his sudden death. The final section would have devoted itself to consider the last things: that of eternal life, of the resurrection, of the vision of God, etc.

This outline of the going out from God and the return to God, which Thomas has already placed in this Commentary on the Sentences, now finds itself in the Summa, especially in the Prima and the Secunda pars. Although it carries traces of neoplatonic thought, at least they are precise. And it has been evidently altered to meet the needs of the history of salvation in the sense that is proper to the divine plan of salvation hidden in the intellect of God from all eternity to which the heart of the schema is analogous and is to be considered a biblical-christian schema. Thomas, therefore, did not write a freewheeling theology autonomously, but he deduced it, adapting it for us from the very history of salvation as he found it. It is significant that the scope of the Summa was to reveal reality as it is seen by God who is the principle and end of everything. This is the same as saying as God conceived it. (God is the subject of theology!)

Within the schema of the Tertia pars and with these visible signs, one is able to return with his own christology (which does not happen easily) to the role of the instrumental cause of the return of all things, both of man and the cosmos, to God. The return, in fact, comes about through the instrumentality of Christ, and not only in the manner of an instrument, but also in the sense that in Him the plan of God comes to its conclusion, properly, through the Incarnation and all the works of the divine incarnate Word in human history. In such a way the final end is referred to the first end, its origin, or -- which is the same thing -- eschatology responds perfectly to the protoword.

The research for the creating and redeeming plan of God profoundly influenced Thomas, who believed, in the end, that he had found it intuitively among the greatest lines of his thought. In the years which followed, the importance of his methodological schema was undervalued in so far as people especially preferred to use the moral theology of the Summa (the Secunda pars), and, what is more, to use it an a strongly synthetic way, leaving out, unfortunately, the more dogmatic parts of the work.

In his time of residence in Rome Thomas also wrote or carried forward the works that he had already begun. There was the Catena aurea mentioned above and the Quaestiones disputatae, De potentia which first analyzes the fact of divine power under every aspect and then takes up Trinitarian themes. There was also the Quaestio disputata De anima and the De spiritualibus creaturis (which includes both men and angels).

The Compendium theologiae, a very valuable work, was written at the request of his closest, faithful and ever present companion, Reginald of Piperno, who was his assistant, first secretary, and the author of many of the sets of notes of Thomas's courses, let alone being his confessor at the time of his Master's death and the one who inherited and was in charge of publishing his works. The Compendium is outstanding for its synthesis, its simplicity and its relative brevity.

Throughout this period there are brief responses to questions debated in theology and given by Thomas to those – often Brothers or the Master General of the Order – who are consulting him. There is the Responsio de articulis 108, the De forma absolutionis, the Responsio de articulis 36, and the Responsio ad articulis 43 . In the latter Thomas very frankly discusses questions that are not theologically or teologically irrelevant, that relate, for example, to a place, either here or there, for example Hell. The De regno ad regem Cypri (incomplete) deals with politics in a pedagogical and moral sense. Finally he began to write the Sententia super de anima, a commentary, probably for his own use, on Aristotle's De anima, in which he utilizes the latest translation from the Latin of the great philosopher.