The aim of this study was to investigate whether a genetic polymorphism of FcγRIII exists in mice, which could explain the different susceptibility to pathogenic IgG anti‐collagen type II (CII) antibodies in mice carrying the collagen‐induced arthritis (CIA)‐susceptible H‐2^q haplotype. The gene for FcγRIII was sequenced in 11 common mouse strains, and the results revealed three different haplotypes of mouse FcγRIII: FcγRIII:V, FcγRIII:H and FcγRIII:T. To study the consequences of this polymorphism, we generated mice carrying the FcγRIII:H haplotype from the CIA‐susceptible, H‐2^q‐positive DBA/1 mouse or the FcγRIII:V haplotype from the CIA‐resistant, H‐2^q‐positive SWR mouse. After CII immunization or transfer of IgG anti‐CII antibodies, FcγRIII:H‐expressing mice, but not FcγRIII:V‐expressing mice, developed progressively severe arthritis. We also investigated if C5, in addition to FcγRIII polymorphism, could affect the susceptibility to the pathogenic IgG anti‐CII antibodies in H‐2^q‐positive mice. Here we show that SWR mice, naturally deficient in C5, can develop CIA when supplemented with C5 and that anti‐C5 antibody treatment of FcγRIII:H‐expressing mice inhibits arthritis development. These data demonstrate for the first time a genetic polymorphism of FcγRIII in mice that may, together with C5, regulate induction of autoimmune disease.