Saint Luke is compositionally very similar to Jan van Eyck's Madonna of Chancellor Rolin (c. 1435, Musée du Louvre, Paris), which was completed in virtually the same period. Presumably, Van der Weyden could have seen Van Eyck's panel in Bruges, before it was sent to Autun in Burgundy, Chancellor Rolin's hometown. Both scenes take place in similarly elegant rooms with tiled floors, tripartite doorways, and two background figures observing a river view. The similarities point to both the inspiration that Rogier seems to have drawn from Van Eyck's work and the innumerable variations he introduced to arrive at his own original composition.
The probable initial location of Van der Weyden's painting in the Brussels painters' guildhouse, or in their chapel in the Cathedral of Saint Gudule (where Van der Weyden was later buried) may account for the three close copies of the work (now in the Hermitage, Saint Petersburg; the Alte Pinakothek, Munich; and the Groenigemuseum, Bruges) that were made in later decades, as well as numerous repetitions or interpretations of individual figures, particularly that of the Madonna and Child.
The Gospel of Saint Luke covered Mary's life in some detail and therefore the saint came to be considered the first to portray her. This work may be the earliest known example to depict Saint Luke creating a portrait in the presence of his sacred models. He is shown kneeling before the Virgin and Child in a richly appointed room, drawing with a metalpoint on a small sheet; beyond them is an enclosed garden, which alludes to Mary's virginity, and two small figures looking out over a parapet at the river lined with urban buildings. The scene underscores the humble, earthly nature of the figures; Mary has no halo or crown, but sits at the foot of the throne, embodying her humility, and breastfeeds the child to highlight their physical connection. The cityscape in the background consists of typical Flemish buildings, suggesting that the scene takes place in surroundings like the viewer's own.
This painting is oil and tempera on oak panel and it is housed in The Museum of Fine Arts, Boston, Massachusetts.