The development of non-Hodgkin's lymphomas (NHL) is one of the major complications of AIDS. Although several biologic aspects of AIDS-related NHL have been clarified, their sensitivity to immune system cytotoxic effectors has not been tested. In this study, we have investigated the susceptibility of one major AIDS-related NHL type, Burkitt's-type lymphoma (BL), to the cytotoxic activity of lymphokine-activated killers (LAK) and prolactin-activated killers (PAK), which were generated from peripheral blood mononuclear cells upon stimulation with interleukin-2 (in the case of LAK cells) and prolactin (in the case of PAK cells). The sensitivity of AIDS-related BL to in vitro raised cytotoxic effectors was compared with that of BL variants of the general population, including sporadic BL and endemic BL. The data show that AIDS-related BL is susceptible to cytolysis by LAK cells, whereas both LAK and PAK cells can efficiently kill endemic BL. In contrast, sporadic BL showed resistance to all cytotoxic effectors tested. Intriguingly, in the case of AIDS-related and endemic BL suboptimal doses of interleukin-2 in combination with prolactin displayed a cytotoxic effect similar to that of LAK cells, suggesting a synergistic activity of the two agents. Overall, these data corroborate the notion that the distinct BL variants differ in their biologic features despite their morphologic and genetic similarity.