CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed on antigen-presenting cells (APCs) and is essential for immune activation. Although agonistic CD40 antibodies have been developed for immunotherapy, their clinical efficacy has been limited. We have found that coengagement of the Fc domain of agonistic CD40 monoclonal antibodies (mAbs) with the inhibitory Fc gamma receptor Fc gamma RIIB is required for immune activation. Direct comparison of mAbs to CD40 enhanced for activating Fc gamma R binding, hence capable of cytotoxicity, or for inhibitory Fc gamma RIIB binding, revealed that enhancing Fc gamma RIIB binding conferred immunostimulatory activity and considerably greater anti-tumor responses. This unexpected requirement for Fc gamma RIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics.