SPRY and B30.2 are homologous domains which can be identified in 11 protein families encoded in the human genome. These include cell surface receptors of the immunoglobulin super-family (BTNs), negative regulators of the JAK/STAT pathway (SOCS-box SSB1-4) and proteins encoded by the numerous TRIM genes. Collectively, proteins containing SPRY and B30.2 domains cover a wide range of functions, including regulation of cytokine signalling (SOCS), RNA metabolism (DDX1, hnRNPs), intracellular calcium release (RyR receptors), immunity to retroviruses (TRIM5alpha) as well as regulatory and developmental processes (HERC1, Ash2L). In order to clarify the evolutionary relationship between the two domains, we compiled a curated database of SPRY and B30.2-domain sequences. We show that while SPRY domains are evolutionarily ancient, B30.2 domains, found in BTN and TRIM proteins, are a more recent evolutionary adaptation, comprising the combination of SPRY with an additional domain, PRY. The combination of SPRY and PRY to produce B30.2 domains may have been selected and maintained as a component of immune defence.