Renal biopsy data indicate that tubular epithelial cells serve as a reservoir for HIV-1 infection. We studied the effect of HIV-1 gp120 envelope gene expression on tubular cell apoptosis. HIV-1 gp120 was expressed in a lentiviral vector pHR-CMV-IRES2-EGFP-DeltaB. This plasmid construct was used to produce pseudotyped virus using VSV-G envelope to enhance the tropism for efficient viral transduction. Human proximal tubular (HK-2) cells were transduced and assayed for cellular injury by trypan blue exclusion, Hoechst and PI staining, TUNEL, and cell cycle staging. HIV-1 gp120-transduced HK-2 cells showed cellular injury in a time-dependent manner. Gp120-transduced cells showed 2.5-fold greater apoptosis when compared with vector-transduced cells. Cell cycle analysis did not reveal any alteration between gp120-transduced cells and vector-transduced cells. Gp120-transduced cells showed higher expression of both Fas and FasL, whereas pretreatment with anti-FasL antibody partially inhibited gp120-induced tubular cell apoptosis. Similarly, pretreatment with caspase-8 inhibitor attenuated gp120-induced HK2 cell apoptosis. Moreover, gp120-transduced cells showed activation of caspase 8. These results suggest that HIV-1 gp120 expression induces tubular cell apoptosis through the extrinsic pathway by enhancing Fas and FasL expression and activation of caspase-8.