In this study, we address the question as to which cell surface receptors expressed on lymphocytes specifically interact with extracellular Trx1 by way of disulfide bond exchange. Using a kinetic trapping technique that enables the detection and isolation of otherwise short-lived reaction intermediates on the surface of intact cells, we identify and validate the tumor necrosis factor receptor superfamily member CD30 (TNFRSF8) as the principal target molecule for Trx1 on infected and transformed lymphocytes. The cell surface activity of Trx1 is highly selective, discriminating between different members of the TNFR superfamily. Trx1-mediated thiol-disulfide exchange leads to a structural change in the CD30 ectodomain that can be detected with conformationsensitive antibodies. We demonstrate that disulfide exchange between Trx1 and CD30 interferes with binding of the CD30 ligand (CD30L) to its cognate receptor and that Trx1 affects CD30-dependent changes in lymphocyte effector function. As CD30 is implicated in both stimulatory and apoptotic signaling, our findings suggest that Trx1 interacts with CD30 to modulate lymphocyte behavior and survival under conditions of infection and inflammation.