Clinical and experimental studies have demonstrated that excessive alcohol consumption can result in impairment of the immune system, and can impact several immune functions including immune tolerance and host defense against opportunistic infections, and development of certain tumors. Although multiple factors are involved in the effects of ethanol on the immune system, several studies implicate chronic activation of immune cells and impairment of thymus-derived lymphocytes (T lymphocytes). Helper CD4⁺ T lymphocytes are the central regulators of the immune system and depletion of these lymphocytes is a major contributing factor in ethanol-induced immune dysfunction and exacerbation of HIV and/or HCV pathogenesis. However, the mechanisms involved in the ethanol induced CD4⁺ T cell depletion have only recently begun to be elucidated. Our work demonstrates that exposure of human CD4⁺ T cells to physiologically relevant concentrations of ethanol leads to the (i) enhanced activation of TNFα-inducible NFκB, the transcriptional regulator of the Fas promoter and ii) increased susceptibility to Fas-and activation-induced apoptotic death via augmentation of caspase 3 activity. Work done by us, and others, on the effects of ethanol on CD4⁺ T cell function and survival strongly suggests that alcohol plays a significant role as a co-factor in HIV and/or HCV pathogenesis.