The effect of cimetidine and ranitidine (histamine type-2 receptor antagonists) on the production of interleukin-2 (IL-2) by mitogen-activated, normal murine spleen cells was studied in vitro. Cimetidine (10(-4) mol/L to 10(-6) mol/L) increased IL-2 production to a maximal 8.8 +/- 1.6 U (IL-2 activity), as compared with media controls of 1 U. Ranitidine (10(-4) mol/L to 10(-6) mol/L) also increased IL-2 production to a maximal 5.6 +/- 1.2 U, as compared with media controls of 1 U. The increases for both drugs were statistically significant- (p at least less than 0.03 for all doses tested). These data suggest that our previously demonstrated immunofacilitation of proliferative and cytotoxic lymphocyte responses by cimetidine was probably mediated by the presence of increased IL-2. These data further suggest that histamine type-2 receptor antagonists may have immunorestorative potential in clinical immunotherapy of IL-2 deficient states.