The T cell surface glycoprotein, CD6 binds CD166 in the first example of an interaction between a scavenger receptor cysteine‐rich domain and an immunoglobulin‐like domain. We report that in human these proteins interact with a K_D =0.4–1.0 μM and K_off ≥0.4–0.63 s^–1, typical of many leukocyte membrane protein interactions. CD166 also interacts in a homophilic manner but with around 100‐fold lower affinity (K_D =29–48 μM and K_off ≥ 5.3 s^–1). At concentrations, that will block the CD6/CD166 interaction, soluble monomeric CD6 and CD166 inhibit antigen‐specific human T cell responses. This is consistent with extracellular engagement between CD6 and CD166 being required for an optimal immune response.