The picture has all the elements of a typical sacra conversazione, with the Madonna enthroned with the child, with St. Francis to the right and St. Nicasius to the left.

Matteo and his brother Bruto Muzio were members of the Knights of Rhodes, whose ensign is borne by St. Nicasius (a martyred saint who had also belonged to the Hospitallier order).

The traditional scheme of composition is lightened by the novel use of such elements as the throne and the landscape, which takes up a good portion of the background.

The altarpiece was commissioned by the condottiero Tuzio Costanzo in memory of his son Matteo, who died of a fever whilst serving the Republic of Venice, in 1499.

After being recovered, it was accurately restored in 2002-2003 by the Accademia Laboratories in Venice and displayed in the major exhibition Le maraviglie dell'arte, before being returned to its home in Castelfranco in December 2005.