Raffaello arrived at Città di Castello from his hometown, Urbino, as a result of the good relations between the Vitelli and the Duke of Urbino, and the need to replace Luca Signorelli who had left Città di Castello to work at Orvieto. He had been an apprentice of Perugino and at the time of his début in Città di Castello he was the head, along with Evangelista da Pian di Meleto, of the Studio inherited from his father Giovanni Santi.
 His first documented painting at Città di Castello was the pannel " S. Nicola da Tolentino" (1500 - 1501) commissioned by Andrea Baronci for a chapel in his name in the church of S. Agostino. Of the large pannel only a few fragments remain today: Virgin Mary, The Lord with cherubs (Naples, Capodimonte Museum), an Angel (Brescia, Pinacoteca Tosio Martinengo), another Angel (Paris, Louvre).
It suffered serious damage during the earthquake of 1789 and was purchased by Pope Pius VI who had it divided in various parts. These fragments were afterwards carried away by the French in 1799 and some of them were lost - S. Agostino crowning S. Nicola, two Angels, the frame, and the background landscape. On the basis of a preliminary sketch by Raffaello (Lille, Wicar Museum) and a copy of a part of it done in 1791 by Ermenegildo Costantini for the church of S. Agostino (today in the Pinacoteca), it was possible to compose an approximate reproduction of the pannel (see illustration). Raffaello's second painting at Città di Castello with a sure date is the Crucifiction (National Gallery, London) commissioned by Domenico Gavari for an altar in the church of S. Domenico in 1503. A dedication inscription remains on the altar of the painting bearing that date. The two works reveal the influence of Perugino.
Raffaello's only painting which still remains in Città di Castello, the Gonfalone of the Holy Trinity, is of uncertain date but generally estimated to be of 1499. This was a year of terrible plague, and the subjects in this painting - S. Rocco and S. Sebastiano, traditionally invoked to exorcise plague - lend support to this date. Stylistic elements in the painting typical of Urbino and Florence, however, could indicate a somewhat later date.
The last work of the painter done at Città di Castello was the Wedding of the Virgin, now at Brera Museum, Milan. This painting was commissioned by the Albizzini family for the altar of S. Giuseppe in the church of S. Francesco where the date, 1504, is inscribed over the altar. At the time of Napoleon's march through Italy, it was given to General Lechi by the town municipality. It was modelled on a like subject done by Perugino for the Cathedral of Perugia in 1503 and now at Caen Fine Arts Museum. Raffaello's interpretation displays greater fantasy with finer prospective and a highly classical approach typical of Florence and Urbino.