We report here a role for cyclic AMP-responsive element-binding protein-1 (CREB-1) in B cell antigen receptor (BCR)-induced growth inhibition by IFN-gamma. BCR-induced proliferation is negatively regulated by IFN-gamma. Stimulation through BCR resulted in dose-dependent induction of CREB-1 binding to the consensus cyclic AMP-responsive element. Recombinant IFN-gamma inhibited the BCR-induced CREB-1 DNA binding activity and cell proliferation in B cells from signal transducer and activator of transcription-1 (STAT-1)(+/+), but not STAT-1(-/-) mice. These studies provide the first evidence for cross-talk between the STAT-1 and CREB-1 signaling pathways in IFN-gamma-mediated negative regulation of B cell activation.