Complement and Fc receptor (FcR)-positive cells mediate effector functions of antibodies. Antibody-dependent immunity against the melanosome membrane glycoprotein gp75/tyrosinase-related protein-1 (TYRP-1) of melanocytes leads to autoimmune hypopigmentation (vitiligo) in mice. Hypopigmentation occurred in mice deficient in activating FcR containing the common γ subunit (FcγR γ^−/−) and in mice deficient in the C3 complement component. Mice doubly deficient in both FcγR γ and C3 did not develop hypopigmentation, suggesting that complement and FcγR formed redundant mechanisms. Following passive immunization with antibody, no further adaptive immune responses were required. Chimeric FcγR γ^−/−,C3^−/− mice reconstituted with bone marrow from either FcγR γ^−/− or C3^−/− mice or adoptively transferred with FcγR γ^+/− macrophages did develop antibody-mediated hypopigmentation. Thus, either complement or macrophages expressing activating FcγR can independently and alternatively mediate disease in a model of autoimmune vitiligo.