SignificanceMany patients with B cell lymphoma carry alterations in the gene coding for the transcription factor Foxp1. High Foxp1 expression has been linked to poor prognosis in those malignancies; however, the physiological functions of Foxp1 in mature B cells remain unknown. By employing genetic mouse models, we show that Foxp1 deletion results in reduced B cell numbers and impaired antibody production upon T cell-independent immunization. Foxp1-deficient mature B cells are impaired in survival and exhibit an increased proliferation capacity, and transcriptional analysis identified defective expression of the prosurvival Bcl-xl gene. Our results provide insight into the regulation of mature B cell survival by Foxp1 and have implications for understanding the role of Foxp1 in the development of B cell malignancies.