B cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other key transcriptional regulators. FOXP1 is a transcription factor that regulates early B cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B cell subpopulations revealed that FOXP1 shows opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. ChIP-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcriptional activator and repressor of genes typically involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in lymphoid cells. These mice exhibited irregular formation of GCs in the spleen, showing a modest increase in naïve and marginal-zone B cells, and a significant decrease in GC B cells. Furthermore, aberrant expression of FOXP1 impaired the transcription of non-coding γ1 germline transcripts (GLTs) and inhibited efficient class-switching to the IgG1 isotype. These studies show that FOXP1 is physiologically down-regulated in GC B cells and that aberrant expression of FOXP1 impairs mechanisms triggered by B cell activation, potentially contributing to B cell lymphomagenesis.