The effect of salazosulfapyridine (SASP) on the antibody response of murine spleen cells in vitro was studied. SASP inhibited the response to sheep red blood cells (SRBC), a T-cell-dependent (TD) antigen, dose-dependently and was most effective at a dose of 2 x 10(-4) M without cell toxicity. No remarkable inhibition was seen with the main metabolites of SASP, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP). SASP failed to inhibit antibody production to T-cell-independent antigens such as dinitrophenyl-Ficoll or trinitrophenyl (TNP)-lipopolysaccharides, although the response to TNP-keyhole limpet hemocyanin, another TD antigen like SRBC, was inhibited. Further, this drug did not show any depression of the anti-SRBC plaque-forming cell (PFC) response in spleen cells treated with anti-Thy1.2 antibody plus complement. The inhibition of anti-SRBC PFC response by SASP was accompanied by a reduction of interleukin 2 (IL-2) secretion. Our results suggest that SASP may act on T cell populations and may inhibit the T-cell-dependent antibody response partly through a depression of IL-2 production. The active compound appears to be SASP itself, rather than its metabolites.