Expression of the for khead transcription factor FOXP1 is essential for early B-cell development, whereas down regulation ofFOXP1at the germinal center (GC) stage is required for GC B-cell function. Aberrantly high FOXP1 expression is frequently observed in diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma, being associated with poor prognosis. Here, by gene expression analysis upon ectopic over expression of FOXP1 in primary human memory B cells (MBCs) and B-cell lines, combined with chromatin immune oprecipitation and sequencing, we established that FOXP1 directly represses expression ofPRDM1, IRF4, andXBP1, transcriptional master regulators of plasma cell (PC) differentiation. Inaccordance, FOXP1is prominently expressed in primary human naïve and MBCs, but expression strongly decreases during PC differentiation. Moreover, as compared with immunoglobulin (Ig)M1MBCs, IgG1MBCscombine lower expression ofFOXP1with an enhanced intrinsic PC differentiation propensity, and constitutive (over)expression of FOXP1 in B-cell lines and primary human MBCs represses their ability to differentiate into PCs. Taken together, our data indicate that proper control of FOXP1 expression plays a critical role in PC differentiation, whereas aberrant expression of FOXP1 might contribute to lymphomagenesis by blocking this terminal B-cell differentiation.