The term 'Byzantine' is used to refer to the art which emanated from the Eastern Christian Empire from the fourth century onwards, the capital of which was Byzantium or Constantinople, now Istanbul in Turkey. Although the term can often refer to a style, rather than a geographic place, Byzantine painting is recognisable by its formulaic appearance, highly-stylised figures and rich colours. This painting is a devotional image known as an icon, a window through which the viewer can interact with the holy subjects within. Icons depict a sacred, infinite, and often miraculous presence, and so resist any reference to a set time or place. Here, the gold background removes the Virgin and Child from everyday, earthly reality. Their haloes are decorated with geometric and floral patterns, lines and holes, which are incised and punched directly into the gold background.

The Virgin of Tenderness in the Royal Collection is a direct copy of the celebrated icon of Notre-Dame de Grâce – often known as The Cambrai Madonna - which was brought from Rome to Cambrai (France) by Fursy de Bruille, a canon of Cambrai Cathedral who had taken part in the Council of Ferrara-Florence in 1438. The icon was later installed in the Chapel of the Holy Trinity in Cambrai Cathedral in 1451, where it was greatly revered. The Royal Collection copy even bears identical dimensions to The Cambrai Madonna.

The Cambrai Madonna, and by proxy the Royal Collection picture, derive from a Byzantine format known as the 'Virgin Eleousa', or the 'Virgin of Tenderness', in which the Virgin and the infant Christ touch their cheeks together in a loving and intimate moment. This format dates back to early Christian times, and became widespread in the Byzantine world in the eleventh and twelfth centuries, with variants continuing to flourish throughout the thirteenth and fourteenth centuries. Here, Christ pulls at his mother's mantle with his left hand, while clutching the Virgin's chin and looking out at the viewer. Supported in his mother's arms, Christ is depicted as a playful, real and weighty baby. This demonstrates a tendency towards a more naturalistic portrayal of the human figure, diverging from the stylized and formulaic figures often present in Byzantine painting. The focus on touch in the picture reminds the viewer that, although Jesus is the Son of God, he was in fact born of human flesh. The conjoined pose – combined with the Virgin's melancholic expression - also foreshadows the death of Christ. Particularly from the latter thirteenth century, the faces of the grieving Virgin and her dead son are often seen pressed together once more in depictions of Christ's Deposition from the Cross, following the Crucifixion.

Although conceived and developed on Byzantine soil, the 'Virgin Eleousa' or the 'Virgin of Tenderness' format attained great popularity in Italy during the thirteenth and fourteenth centuries. Byzantium and Italy had always experienced close connections, which facilitated both commercial and cultural exchange. In recent times, The Cambrai Madonna has been widely considered to be an Italian copy after an earlier Byzantine icon, likely produced in Siena, perhaps from the circle of the Lorenzetti brothers in the second quarter of the fourteenth century. The strikingly narrowed eyes of the Virgin here differ from the larger, flatter eyes of Byzantine painting. Along with the sturdy, weighty quality of the figures, these stylistic traits certainly suggest that the painter may have had links to artists working in the Tuscan tradition in thirteenth- and fourteenth-century Italy. However, unusual aspects of the painting's materials and techniques suggest a departure from a purely Italian approach, as a result of which The Cambrai Madonna is often termed 'Italo-Byzantine'.

While the copy in the Royal Collection is typically 'Italo-Byzantine' in style, it should also be considered that the painting may have been produced not by an artist working in the Italian/Byzantine tradition, but rather by a Netherlandish artist. The Cambrai Madonna would become an important prototype for images of the Virgin and Child in the Low Countries. Soon after The Cambrai Madonna was installed in the Cathedral, many initial copies were commissioned, and produced by Netherlandish artists including Petrus Christus and Hayne of Brussels. While not all versions strictly retained the Byzantine style, other direct copies akin to the Royal Collection picture can be found in the Musée Royaux des Beaux-Arts in Brussels (Netherlandish?: dated to the mid-seventeenth century) and in the Eglise St-Martin in Frasnes-lez-Buissenal in Belgium (dated mid-fifteenth century).  The earliest paintings on a copper support date from the late sixteenth century, so it is likely that the Royal Collection picture dates from the seventeenth century, comparable to the aforementioned version in Brussels.