In the peripheral immune system, apoptosis is involved in the down-regulation of immune reactions, acting as a homeostatic mechanism to limit the expansion of activated lymphocytes, for example in viral diseases. We previously reported that uninfected T lymphocytes from HIV-infected persons were highly prone to in vitro spontaneous apoptosis which was increased following TCR-dependent or independent activation. The present report reviews recent data suggesting that the chronic stimulation of the immune system in HIV infection induces a dysregulation in the expression of molecules involved in cell survival (Bcl-2) or cell death (Fas), promoting an exacerbated peripheral cell death in blood and lymph nodes, possibly contributing to the loss of both functional cytotoxic and helper T lymphocytes in AIDS.