Infection with human immunodeficiency virus (HIV) results in the progressive destruction of CD4 T lymphocytes, generally associated with progression of the disease. The progressive disappearance of CD4 T lymphocytes leads to the lack of control of HIV replication and to the development of severe immune deficiency responsible for the occurrence of opportunistic infections associated with AIDS. In this review we discuss premature lymphocyte apoptosis in the context of HIV infection as the consequence of the continuous production of viral proteins, leading to an unbalanced immune activation and to the triggering of apoptotic programs. The chronic immune activation induces the continuous expression of death factors which could turn lymphocytes, including CD4 T cells, CD8 CTL or APC, into effectors of apoptosis, leading to the destruction of healthy activated non‐infected cells. Thus, programmed cell death would significantly contribute to peripheral T cell depletion in AIDS, particularly if the Th cell renewal is impaired. Under potent anti‐retroviral therapies, a complete normalization of lymphocyte apoptosis is observed, concomitant with a partial restoration of the number and the functions of the immune system.