A role for the dietary trace mineral element selenium in the reduction of cancer incidence has been documented in numerous epidemiological and experimental studies. The precise mechanism of this antitumor effect is not well understood, but published data suggest that both inhibition of tumor cell growth and enhancement of host immunity are likely to be involved. In this study we report that selenium at physiologic concentrations can inhibit human lymphocyte proliferation in response to irradiated tumor cells in mixed lymphocyte/tumor cell cultures (MLTC). In addition, we demonstrate that the various lymphocyte functional activities generated in these cultures exhibit different levels of sensitivity to the effects of selenium. The generation of suppressor-cell activity in MLTC was strongly inhibited by the presence of physiologic levels of selenium, while the development of cytotoxic T-lymphocyte activity in identical cultures was not affected by selenium. Production of interleukin-2 in these cultures showed an intermediate sensitivity to the effects of selenium. Thus, selenium appears to be capable of selectively regulating the generation of functional lymphocyte subsets in vitro. Such selective regulation could explain the published effects of selenium on immunity and would be consistent with a role for immunity in the observed reduction of cancer incidence associated with elevated selenium intake.