The effect of cimetidine, an H-2 receptor antagonist, on activation of PBL from both normal individuals and melanoma patients was studied. It has been shown that cimetidine enhanced, though moderately, the production of TCGF from normal PBL after PHA-P stimulation. In addition, cimetidine significantly augmented TCGF-induced proliferation of normal PBL, as well as proliferation induced by allogeneic cells (MLC) by PPD, Con A, and PHA. In PBL samples where coincubation with cimetidine had limited or no effect, preincubation of PBL with cimetidine prior to the addition of IL-2 and other T cell activators showed a significant enhancement effect. This effect mediated by cimetidine was further demonstrated on PBL from melanoma patients whose T cell responses were initially low. The possibilities are discussed that: (a) cimetidine treatment inactivates suppressor cell activity, thus enhancing T cell mediated responses; or (b) cimetidine may act directly at effector cell level.