The length of time taken over the Borgo Madonna makes it difficult to know what his early style was like, but the Baptism in London (NG) is accepted as an early work, showing traces of Florentine (and Sienese) influence, yet standing for a calm and classic stillness totally opposed to all that the Florentines then sought. A St Jerome at Berlin, signed and dated 1450, is unfortunately too damaged for use in stylistic comparisons, but a damaged fresco of 1451 in S. Francesco at Rimini, Sigismondo Malatesta and His Patron Saint, shows Piero's love of symmetry and of counterchanged patterns in the two dogs. By this time he had probably painted some frescoes, now lost, in Ferrara, the influence of which is discernible in the style of the local school. About 1452 Piero began the work on which his fame chiefly rests, the fresco cycle in the choir of S. Francesco at Arezzo depicting the story of the True Cross. The narrative is highly complicated, being based on several different accounts in the Golden Legend, and it is not made easier to follow by the fact that Piero, presumably for artistic reasons, has treated the story in a cavalier way and arranged, for example, the two battle scenes out of order in the story but facing each other at the bottom of each of the side walls, thus forming one of the symmetries he loved. The frescoes were almost unknown for centuries and suffered from neglect, but at least they were not repainted much and therefore give a good idea of Piero's mature style, and of what he owed to Domenico Veneziano and to Florence. In 1459 Piero was in Rome, by which time the Arezzo frescoes were presumably finished. The work in the Vatican which Piero is known to have done has vanished, but a St Luke in S.M. Maggiore is, perhaps optimistically, ascribed to him. The ascription is not made any more plausible by the fact that two of his masterpieces are likely to date from this time — the fresco of The Resurrection in Borgo and the diptych with the portraits of his friends and patrons the Duke and Duchess of Urbino (Florence, Uffizi). The portraits have been associated with a poem of 1465, but look stylistically rather later (c.1472?). They show strong influence from Flemish painting in the use of the oil technique, perhaps due to the presence of Flemish pictures in Italy. Later on, Joos van Ghent worked at Urbino. The curious Flagellation of Christ, which again shows Flemish influence, was also painted for Urbino. Various explanations of the subject and date have been advanced. All this time Piero was working on a large altarpiece, parts of which survive. It was commissioned for Borgo San Sepolcro in 1454 and completed fifteen years later: the centre panel was probably a Madonna but is now lost; on either side were Sts Augustine, Michael, John (?), and Nicholas of Tolentino, now in Lisbon, London (NG), New York (Frick Coll.) and Milan (Poldi-Pezzoli). The last two pictures Piero painted are the Madonna with the Duke of Urbino as Donor (Milan, Brera), known as the Brera Madonna, which is datable between c.1472 and c.1475, and the unfinished Nativity (London, NG). It is sometimes said, on exiguous evidence, that the hand (or even the head) of the Duke in the Brera Madonna is by Berruguete. In any case, it seems clear that Piero stopped painting in the 1470s - the last document to record him as a painter is of 1478, concerning a lost fresco - although he lived on until 1492. One explanation for this is that he became increasingly interested in perspective and mathematics, for he wrote two treatises, De prospectiva pingendi and De quinque corporibus regularibus, and it is also likely that his sight failed, for he seems to have been blind in his last years. His chief pupils were Perugino and Signorelli, both of whom reacted against his style.

There are other works by him in Arezzo, Boston (Gardner), Monterchi nr Sansepolcro, Oxford (Ch. Ch.), Perugia, Sansepolcro, Urbino, Vaduz (Liechtenstein Coll.), Venice (Accad.) and Williamstown Mass.