B lymphocytes are an integral part of the adaptive immune system. Upon antigen binding to the B cell receptor (BCR), B cells rapidly proliferate and differentiate into antibody-secreting plasma cells. The p38 mitogen activated protein kinase (MAPK) pathway functions downstream of the BCR to control cell proliferation, but the transcriptional effectors of this pathway in B cells have remained elusive. The MADS domain transcription factor MEF2C functions as a signal-dependent transcriptional switch to control a wide array of developmental and physiological processes. In addition to its established role in muscle and neural lineages, MEF2C is also expressed in B cells, but its function in that lineage had not been determined previously. In the present study, we inactivated Mef2c exclusively in B cells by conditional gene targeting in mice. Loss of MEF2C function resulted in a reduced immune response to antigen and a severe defect in B cell proliferation, and we show that MEF2C regulates proliferation in response to BCR stimulation via the p38 MAPK pathway. These studies establish MEF2C as an important regulator of B cell proliferation in response to BCR stimulation via its role as a downstream transcriptional effector of the p38 pathway.