The human immunodeficiency virus (HIV) may interact with the Epstein Barr virus (EBV) indirectly by effects on the T4 lymphocyte or directly by effects on EBV transformed B lymphocytes. We have confirmed the susceptibility of EBV transformed B lymphocytes to productive HIV infection, and have evaluated the cytotoxic activity of HIV seronegative and seropositive donors after sensitization by their autologous EBV infected (monoinfected) or EBV and HIV infected (coinfected) transformed cell lines in a 51Cr release cytotoxicity assay. When sensitized by the coinfected cell line and assayed against monoinfected and coinfected cell lines, the cytotoxic activity of the seronegative donors was inhibited when compared to the cytotoxic effectors sensitized by the monoinfected B cell line. The inhibition appeared to be unrelated to direct HIV infection of the T4 effector cells and was reversible by addition of recombinant interleukin-2. Although deficient in their EBV cytotoxic activity in comparison to the seronegative donors, the HIV seropositive donors lysed the coinfected cell line better than the monoinfected cell line, whether or not HIV superinfected cells were used during the sensitization phase. In HIV seronegative donors, HIV may inhibit the immune response to EBV transformed B lymphocytes. This inhibition is not observed in HIV seropositive donors. These studies suggest the development of cytolytic effector mechanisms directed at HIV infected cells during HIV infection.