St. Sebastian was a Roman military officer martyred about AD 300 by being shot full of arrows and then clubbed to death. He was prayed to for protection against the plague. This painting depicts one instance of his intercession. According to legend, this event occurred long after the saint's death, during an outbreak of the Black Death in 7th-century Pavia, Italy. Here – just as a victim is to be buried – a grave attendant is struck by the disease. The plague – or Black Death – devastated Europe for centuries, and the painting's viewers would have known its horrors.

Above in the sky, St. Sebastian, pierced with arrows, kneels before God to plead on behalf of humanity, while an angel and a demon battle it out. The artist was never in Italy and based the appearance of Pavia on that of Avignon.

In 1497, Lieferine contracted with the Confraternity of St. Sebastian to paint this altarpiece dedicated to their patron saint in the church of Notre-Dame-des-Accoules (destroyed during the French Revolution; only the bell tower remains) in Marseille, France. Six other panels from this altarpiece are now in the Philadelphia Museum of Art (Johnson Collection), the Museo di Palazo Venezia in Rome, and the Hermitage Museum in Saint Petersburg.