Recombinant-derived interferon-gamma (reIFN-gamma) was found to inhibit B cell proliferation that was stimulated by soluble goat anti-mouse IgD or goat anti-mouse IgM antibodies, but not that stimulated by Sepharose-bound anti-Ig antibodies. Recombinant IFN-gamma also inhibited the BSF-1-enhanced soluble anti-Ig B cell proliferation but did not block BSF-1 enhancement of Sepharose anti-Ig-stimulated B cell DNA synthesis. Recombinant IFN-gamma concentrations as low as 0.001 U/ml were effective in suppressing the soluble anti-Ig-stimulated B cell proliferative response, and this inhibitory effect could be partially reversed by co-culture with a hybridoma anti-IFN-gamma antibody. Recombinant IFN-gamma appeared not to inhibit action of resting B cells from G0 to early G1, because it did not inhibit the increases in cell size that were stimulated by anti-delta antibody. However, it was effective in partially suppressing the anti-delta-induced increases in expression of B cell surface Ia. For reIFN-gamma to exert its maximum suppressive effect, it had to be added within the first 7 hr after the onset of culture with anti-Ig. Because reIFN-gamma is a lymphokine that can be detected in vivo, we suggest that it may play a key role in influencing physiologic B cell activation that is induced by antigens or immune complex-mediated cross-linking of surface Ig.