One of Piero della Francesca's earliest artworks is the Polyptych of the Misericordia at Sansepolcro. The central panel is the Madonna della Misericordia (Madonna of Mercy). In this panel we see the mercifully protective gesture of the Madonna enfolding her followers in her mantle.

In 1445 the Compagnia della Misericordia, a confraternity of Borgo San Sepolcro, commissioned Piero to paint a polypych for them. According to the taste of the time, the polyptych was to be painted with precious colours and have a solid gold background. Piero did not respect the three year time limit set down in the contract - he was busy working on many other projects. The polyptych was only finished seventeen years later in 1462.

The oldest two panels, to the left of the main panel, depict St. Sebastain and St. John the Baptist. In St. Sebastian we see a close connection with Masaccio's nudes. Piero painted the outlying panels of the tympanum later; including the Crucifixion at the top centre, St. Benedict, the Angel, the Madonna of the Annunciation, and St. Francis in the sides. Towards 1450 Piero finished the figures of St. Andrew and St. Bernardino.

The last part of the polyptych to be painted was the main central panel showing the Madonna della Misericordia. Piero resolves the difficulty of dealing with a flat solid gold background, requested by the patrons, by placing the kneeling members of the confraternitas (who commissioned the altarpiece) in the realistic space created by the Madonna's mantle, a space resembling the apse of a church.