The contribution of Fc-mediated effector functions to the therapeutic efficacy of some monoclonal antibodies has motivated efforts to enhance interactions with Fcγ receptors (FcγR). Although an early goal has been enhanced FcγRIIIa binding and natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), other relevant cell types such as macrophages are dependent on additional activating receptors such as FcγRIIa. Here, we describe a set of engineered Fc variants with diverse FcγR affinities, including a novel substitution G236A that provides selectively enhanced binding to FcγRIIa relative to FcγRIIb. Variants containing this substitution have up to 70-fold greater FcγRIIa affinity and 15-fold improvement in FcγRIIa/FcγRIIb ratio and mediate enhanced phagocytosis of antibody-coated target cells by macrophages. Specific double and triple combination variants with this substitution are simultaneously capable of exhibiting high NK-mediated ADCC and high macrophage phagocytosis. In addition, we have used this unique set of variants to quantitatively probe the relative contributions of individual FcγR to effector functions mediated by NK cells and macrophages. These experiments show that FcγRIIa plays the most influential role for macrophages and, surprisingly, that the inhibitory receptor FcγRIIb has little effect on effector function. The enhancements in phagocytosis described here provide the potential to improve the performance of therapeutic antibodies targeting cancers. [Mol Cancer Ther 2008;7(8):2517–27]