Fas apoptosis inhibitory molecule (FAIM) was cloned as a mediator of Fas resistance that is highly evolutionarily conserved but contains no known effector motifs. In this study, we report entirely new functions of FAIM that regulate B cell signaling and differentiation. FAIM acts to specifically enhance CD40 signaling for NF-kappaB activation, IRF-4 expression, and BCL-6 down-regulation in vitro, but has no effect on its own or in conjunction with LPS or anti-Ig stimulation. In keeping with its effects on IRF-4 and BCL-6, FAIM overexpression augments the plasma cell compartment in vivo. These results indicate that FAIM is a new player on the field of B cell differentiation and acts as a force multiplier for a series of events that begins with CD40 engagement and ends with plasma cell differentiation.