The present invention is related to enhancing the function of anti-tumor antibodies by regulating Fc.gamma.RIIB-mediated activity. In particular, disrupting SHIP activation by Fc.gamma.RIIB enhances cytotoxicity elicited by a therapeutic antibody in vivo in a human. The invention further provides an antibody, e.g., an anti-tumor antibody, with a variant Fc region that results in binding of the antibody to Fc.gamma.RIIB with reduced affinity. A variety of transgenic mouse models demonstrate that the inhibiting Fc.gamma.RIIB molecule is a potent regulator of cytotoxicity in vivo.