The expression of membrane-bound Fas ligand (FasL) and Fas in lymphocytes and monocytes and levels of soluble forms of FasL (sFasL) and Fas (sFas) in plasma from human immunodeficiency virus (HIV)-positive and -negative subjects was evaluated. Surface FasL was detectable on monocytes, but poorly so on lymphocytes, even in the presence of KB8301, a metalloproteinase inhibitor. Unexpectedly, monocytes of HIV-positive subjects expressed less FasL than those of HIV-negative volunteers. sFasL levels in plasma of HIV-positive persons were elevated and correlated with levels in plasma and with HIV RNA burden. sFas levels in plasma of HIV-positive subjects were also elevated and correlated with Fas expression in apoptotic lymphocytes. Finally, culture-induced lymphocyte apoptosis of HIV-positive subjects was enhanced by anti-Fas agonistic antibody but was not inhibited by anti-FasL blocking antibodies. These results suggest that significant dysregulation of both Fas and FasL occurs in HIV infection and contributes to increased sensitivity of lymphocytes to apoptosis.