Epstein-Barr virus (EBV) infection of stimulator cells significantly increased the proliferative response of T cells in the autologous mixed lymphocyte reaction (AMLR). The addition of a monoclonal anti-HLA-DR antibody toAMLR cultures in which either EBV-infected or non-infected non-T cells wereused as stimulator cells strongly inhibited the proliferative response irrespective of the presence of EBV. It is concluded that EBV does not by itself activate the responding cells and that HLA-DR antigens are necessary to trigger T cells. Increased generation of suppressor T cells, determined in both alloantigen-induced DNA synthesis and pokeweed-mitogen-stimulated immunoglobulin production, was found after an EBV infection of stimulator cells. Similarly, EBV-infected non-T cells significantly increased the generation of killer T cells, determined in three different types of target cells: phytohaemagglutinin-stimulated mononuclear cells, EBV-transformed cells, and con-canavalin-A-activated murine spleen cells. The increased T-cell responses after an EBV infection may reflect the attempts in vivo to control andhold in check the viral infection.