Immune complex-mediated inflammatory responses are initiated by FcγR on phagocytes. We report in this study that an inhibitory receptor, FcγRIIb2, is expressed on circulating human monocytes, and when co-cross-linked with stimulatory FcγR it down-regulates effector function. FcγRIIb2 expression is increased by IL-4 and decreased by IFN-γ, in contrast to the activating receptor, FcγRIIa, which is increased by IFN-γ and decreased by IL-4. Thus, Th1 and Th2 cytokines differentially regulate the opposing FcγR systems, altering the balance of activating and inhibiting FcγR. The detection and cytokine modulation of FcγRIIb2 in human myeloid cells provide evidence of a negative regulator of immune complex-mediated responses in human phagocytes and offer a new approach to limit Ab-triggered inflammation in autoimmune disease.