B cell activation by surface immunoglobulin (sIg) cross-linking is accompanied by transient expression of the c-fos protooncogene. This expression is strictly controlled in the B cells. To investigate a biological implication of the c-fos expression in the process of B cell activation by sIg cross-linking, we examined the proliferation of splenic B cells from H2-c-fos transgenic mice. Constitutive expression of the c-fos gene perturbs de novo synthesis of RNA and DNA in the B cells stimulated with anti-IgM antibody. Early events of signal transduction such as an increase in intracellular free calcium level and an induction of the endogenous immediate early genes (c-fos and c-myc) were apparently intact in those B cells. When the sIg stimulation of B cells was mimicked by the costimulation with 12-O-tetradecanoylphorbol 13-acetate and ionomycin, H2-c-fos B cells required higher concentrations of ionomycin for the optimal proliferative responses, suggesting that calcium-dependent signal transduction pathways are disturbed in those B cells. These results demonstrate a novel regulatory effect of c-fos protein on the proliferation of B cells mediated by sIg cross-linking.