We have previously shown that the carboxyl-terminal region of human immunodeficiency virus type 1 (HIV-I) Nef antigen present on the outer surface of virus-infected cells has affinity for uninfected T cells, Here, the in vitro cytotoxic potential of HIV-1 Nef on the T cell surface against CD4+ T cells was investigated in detail, Human T cells expressing Nef on the cell surface by transfection with non-infectious mutant HIV-1 proviruses were demonstrated to kill CD4+ T cells effeciently, Furthermore, it was shown that the carboxyl-terminal portion of Nef was cytotoxic for CD4+ T cells and that monoclonal antibody against the carboxyl-terminal region of Nef inhibited Nef induced-cytolysis, Thus, we concluded that Nef protein on CD4+ T cells may play an important role in the specific loss of CD4+ T lymphocytes during HIV-1 infection.