Tat protein of human immunodeficiency virus type-1 (HIV-1) plays a central role in viral replication and shows pleiotropic effects on the survival and growth of different cell types. Remarkably, Tat represents the first example of a viral protein, that can also be actively secreted by infected cells and shows a cytokine-like activity on both HIV-1 infected and uninfected cells. We previously reported that the stable expression of tat cDNA rescues Jurkat cell lines from apoptosis induced by a variety of stimuli, such as serum withdrawal, engagement of fas antigen or even a productive infection with HIV-1. These findings suggested that Tat was able to modulate the expression of one or more gene(s) relevant for the control of cell survival/death. Consistently, Jurkat cells stably transfected with tat show an upregulated expression of bcl-2. It is still unsettled whether Tat affects cell survival and bcl-2 expression directly or indirectly, modulating the expression of other cellular genes involved in the control of cell survival or encoding for cytokines. Blocking experiments performed with anti-Tat neutralizing antibodies revealed that TAt increases bcl-2 expression and prevent lymphoid T cells from apoptosis by acting, at least in part, through an autocrine/paracrine loop. While high (nM-microM) concentrations of extracellular Tat display a cytotoxic activity on the antigen-mediated induction of T cell proliferation, low (pM) concentrations of Tat were able to protect both Jurkat cells and primary peripheral blood mononuclear cells from apoptosis. Significantly, pM concentrations of Tat were detected in the sera of some HIV-1 infected individuals as well as in the culture supernatant of HIV-1 infected cells, raising the possibility that these levels of Tat protein may be present physiologically in vivo. The potential relevance of Tat-mediated upregulation of bcl-2 for the pathogenesis of HIV-1 disease is discussed.