c-FLIPL, an inhibitor of caspase 8, is known to inhibit the Fas/caspase 8 apoptotic pathway; however, its involvement of Bax/mitochondrial apoptosis is not well understood. Using human cells, Jurkat cell line, induced with HIV-1 gp120, we studied the effects of c-FLIPL on Bax/mitochondrial apoptosis. We found that the induction of apoptosis by HIV-1 envelope protein, gp120, involved the activation of both Bax-dependent and death receptor-mediated pathways, and HIV-1 infection deceased c-FLIPL expression. Interestingly, c-FLIPL expression downregulated protein kinase C (PKC) expression at the transcript level involving activated protein-2 (AP-2). c-FLIPL expression reduced AP-2 protein levels required to promote PKC protein expression and PKC-associated inactive form of Bax, and inhibited Bax activation, suggesting that c-FLIPL inhibits Bax activation via modulating PKC expression at the transcriptional level involving AP-2 during gp120 treatment. Collectively, these findings further corroborate the concept that gp120 plays an important role, via involvement of molecules such as c-FLIPL, in apoptotic cell death due to HIV-1 infection.