The molecular mechanism of human immunodeficiency virus type 1 (HIV-1 gp120)-induced apoptosis in bystander T cells is not well defined. Here, we demonstrate that CD45, a key component of the TCR (T cell receptor) pathway, plays a crucial role in the apoptosis induced by HIV-1 gp120. We observed that HIV-1 gp120-induced apoptosis was significantly reduced in the CD45 deficient cell line and that reconstitution of CD45 in these cells restored the gp120 apoptosis. However, expression of a chimeric protein containing only the intracellular phosphatase domain was not able to restore the apoptotic function in the CD45 negative clone, indicating an important role for the extracellular domain of CD45 in this function. The role of CD45 in gp120-induced apoptosis was further confirmed in T cell lines and peripheral blood mononuclear cells (PBMCs) using a selective CD45 inhibitor as well as CD45 specific siRNA. We also observed that gp120 treatment induced an association of CD45 with the HIV coreceptor, CXCR4. Further elucidation of downstream signaling events revealed that CD45 modulates HIV-1 gp120- apoptosis by regulating Fas ligand induction and activation of the PI-3 kinase/Akt pathway. These results suggest a novel CD45-mediated mechanism for HIV envelope-induced apoptosis in T cells.