Protective humoral immune responses critically depend on the optimal differentiation of B cells into Ab-secreting cells. Because of the important role of Abs in fighting infections and in successful vaccination, it is imperative to identify mediators that control B cell differentiation. Activation of B cells through TLR9 by CpG-DNA induces plasma cell differentiation and Ab production. Herein, we examined the role of the peroxisome proliferator-activated receptor (PPAR) γ/RXRα pathway on human B cell differentiation. We demonstrated that activated B cells up-regulate their expression of PPARγ. We also show that nanomolar levels of natural (15-deoxy-Δ 12, 14-prostaglandin J 2) or synthetic (rosiglitazone) PPARγ ligands enhanced B cell proliferation and significantly stimulated plasma cell differentiation and Ab production. Moreover, the addition of GW9662, a specific PPARγ antagonist, abolished these effects. Retinoid X receptor (RXR) is the binding partner for PPARγ and is required to produce an active transcriptional complex. The simultaneous addition of nanomolar concentrations of the RXRα ligand (9-cis-retinoic acid) and PPARγ ligands to CpG-activated B cells resulted in additive effects on B cell proliferation, plasma cell differentiation, and Ab production. Furthermore, PPARγ ligands alone or combined with 9-cis-retinoic acid enhanced CpG-induced expression of Cox-2 and the plasma cell transcription factor BLIMP-1. Induction of these important regulators of B cell differentiation provides a possible mechanism for the B cell-enhancing effects of PPARγ ligands. These new findings indicate that low doses of PPARγ/RXRα ligands could be used as a new type of adjuvant to stimulate Ab production.