By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/αA, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell–independent type II antigens, as well as IgG3⁺ plasmablast formation. Mice bearing NFATc1^−/− B cells harbor twofold more interleukin 10–producing B cells. NFATc1^−/− B cells suppress the synthesis of interferon-γ by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1^−/− B cells are caused by decreased BCR-induced Ca²⁺ flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/αA expression, NFATc1 controls the Ca²⁺-dependent Cn–NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation.