This article forms an investigation of seventeenth-century Bolognese artist Guido Reni’s use of silk as a painting support. Despite the high cost of the fabric when compared to conventional canvas materials such as linen, Reni chose to utilise silk supports in several large-scale commissions. The article examines seventeenth-century descriptions of Reni’s works on silk, and suggests possible structural reasons for the artist’s choice to use the unusual support, including his reported belief that it was more durable than linen canvas, and investigates whether such a belief has any scientific basis. It also considers aesthetic and symbolic underpinnings that might provide explanation for this practice, including potential associations with Italy’s 1629–1631 plague epidemics.