The basilica was constructed in the fourth century and is recorded as the Titulus Crescentianae, thus relating the church to a certain Crescentia (possibly a Roman woman who founded the church.) According to tradition, the church was established by Pope Anastasius I (399–401).
San Sisto was rebuilt in the early 13th century by Pope Innocent III. The current church is the result of the restorations of Pope Benedict XIII in the 18th century, which left only the bell tower and the apse from the medieval church.
A 13th-century fresco cycle depicting scenes from the New Testament and the Apocrypha has been preserved.
Pope Honorius III entrusted the reform of the monastery at San Sisto Vecchio to Dominic in the 1220s, intending it as part of the reformation of women's religious life in Rome. In 1219 Honorius then invited Dominic and his companions to take up permanent residence at the ancient Roman basilica of Santa Sabina, which they did in the early 1220. After that they founded a convent and studium on June 5, 1222, thus forming the original studium of the Dominican Order in Rome, out of which the 16th-century College of Saint Thomas at Santa Maria sopra Minerva and the Pontifical University of Saint Thomas Aquinas (Angelicum) would grow.[relevant?][1]
Dominican nuns still occupy the monastery at San Sisto Vecchio.[2]
The following persons are known to have been Cardinal priests of S. Sisto (italics are used to denote special cases):[3][4][5][6]
Joannes (attested only at the beginning of 1069).
Petrus (attested from 1100 to 1112).
Sigizo (attested from 1118 to 1130), Roman. He followed Pope Anacletus II in the Schism of 1130–1139.
Pierre Mandonnet, O.P., St. Dominic and His Work, Translated by Sister Mary Benedicta Larkin, O.P., B. Herder Book Co., St. Louis/London, 1948, Chapt. III, note 50: "If the installation at Santa Sabina does not date from 1220, at least it is from 1221. The official grant was made only in June, 1222 (Bullarium O.P., I, 15). But the terms of the papal bull show that there had been a concession earlier. Before that concession, the Pope said, the friars had no hospitium in Rome. At that time St. Sixtus was no longer theirs; Conrad of Metz could not have alluded to St. Sixtus, therefore, when he said in 1221: "the Pope has conferred on them a house in Rome" (Laurent no. 136[full citation needed]). It is possible that the Pope was waiting for the completion of the building that he was having done at Santa Sabina, before giving the title to the property, on June 5, 1222, to the new Master of the Order, elected not many days before." "Work III: Years of Experimental Activity (1215-19)". Archived from the original on 2012-06-18. Retrieved 2013-02-07. Accessed 2012-5-20.