The influence of human seminal plasma (SP) and whole semen (S) on the expression of natural cytotoxicity by human peripheral blood mononuclear cells (PBMNC) was examined. Marked suppression of natural cytotoxicity against K562 targets was observed when effectors were pre-treated for 1 h with SP or S diluted up to 1:400. Abrogation of cytolytic activity by SP was not the result of direct lymphotoxicity, although a reduction of approximately 50% in the number of target binding cells was observed. In addition, the cytotoxicity of interferon (alpha-IFN, beta-IFN, gamma-IFN) and interleukin 2 (IL-2) activated human PBMNC was suppressed by components present in human SP, although IL-2 activated human PBMC were relatively resistant to suppression compared with other effector (spontaneous or activated) populations. Following 1 h exposure to SP, PBMNC failed to recover more than 25% of their initial cytotoxic potential upon further in vitro incubation (18 h) in the absence of SP. However, both interferon and IL-2 caused an increase in the cytotoxicity of these populations, in some instances to the level obtained with control, IFN or IL-2 activated PBMNC. The biological significance of SP as an inhibitor of immune function under experimentally defined conditions is discussed in relation to its possible role in vivo.