The Virgin Mary holds the naked infant Christ who sits on a pillow on a coffin. The elderly Saint Jerome clasps his hand to his chest and contemplates a figure of Christ on the Cross with great sorrow as a tear falls from his eye. The younger saint holding the white lilies is Saint Nicholas of Tolentino, an Augustinian friar who wears the black robes of his Order. He has a sacred radiance glowing on his chest, which refers to the star that shot forth from Sant'Angelo where he was born, and stood over the city of Tolentino, where he settled.

The coffin on which the infant Christ sits is a unique addition, not found in any other Renaissance painting of the Virgin and Child with saints. It indicates Christ's acceptance of and conquest over death. It was common to include emblems of Christ's Passion in images of him as an infant, for example a goldfinch, a lamb, or carpenter's tools such as a hammer or nails. Meditation on Christ's death encouraged understanding of his suffering for humanity's redemption. There seems to be some connection between this image and Lotto's panel of a nude putto crowning a skull with a laurel garland, now at Alnwick Castle. The putto has a similar anatomy and attitude to the Christ Child, the skull rests on a large white cushion and there is a similar landscape in the background. That picture is likely to be a memento mori, a reminder of the inevitability of death.

There is another higher-quality and better-preserved version of this painting at the Museum of Fine Arts, Boston. Lotto appears to have worked on both pictures at the same time, drawing and resolving the composition in the Boston version and then reproducing it on the National Gallery’s canvas, which is signed and dated 'Laurentius Lotus 1522'. The layer structure of the paint and the materials are identical in both versions, as are many of the changes to the composition, known as pentimenti. The pictures were probably painted towards the end of the period that Lotto spent mainly in Bergamo. There is a third version of the painting in the Palma Camozzi Vertova Collection, Bergamo, which has a similar Virgin, child and coffin but different saints (Saint John the Baptist and Saint Catherine of Alexandria) and which is also signed and dated 1522.

The practice of painting two versions of a picture at the same time was common when artists were painting for the market rather than on commission, and the Virgin and Child with saints was a typical repertoire subject in artists' workshops. Saint Nicholas of Tolentino appears relatively rarely in paintings for private devotion and it is possible that the patron of the Boston version wanted a copy of the picture to present to a relative or friend. It is also possible that Lotto made it for himself, to have a copy of the composition for future reference. The Boston version of Lotto's picture is surely the prime version, not only because it was worked out first but also because it was painted with the more expensive pigment of ultramarine; the blue in our version is cheaper azurite. It is likely that when the two paintings were made it was decided that one of them should cost less than the other.

Style: High Renaissance