Abstract Unlike humans, FcμR expression in mice is restricted to B cells with a hierarchy of cell surface expression level: follicular > marginal zone (MZ) > newly formed in spleen and B-2 = B-1a > B-1b in peritoneal cavity. To define the in vivo function of FcμR, Fcmr-deficient (KO) mice were generated by gene targeting. While total splenic CD19+ B and CD3+ T cell-numbers were comparable in KO and littermate control (WT) mice, MZ B cells were reduced ~4 fold and B-1 cells were increased ~2 fold in KO as compared with WT mice. Both serum IgM and IgG3 antibody (Ab) levels in naïve animals were significantly elevated in KO than WT mice. IgM and IgG3 natural Abs reacting with the nucleus or cytoplasm of HEp-2 cells were also elevated in KO mice. When immunized i.p. with a live avirulent strain of S. pneumoniae (R36A), much more robust and long-lasting IgM, IgG3 and IgA Ab-responses to phosphorylcholine developed in KO at low doses of R36A compared with WT. By contrast, when immunized i.p. with nitrophenyl (NP)-coupled chicken γ-globulin in alum, primary IgM anti-NP responses were comparable in both groups of mice, but secondary IgM responses were significantly impaired in KO mice. In contrast, the primary IgG1 anti-NP responses were impaired in KO, however secondary IgG1 responses were indistinguishable in both KO and WT mice irrespective of the antigen dose. These results show that Fcmr ablation results in altered Ab responses to both T-independent and -dependent antigens.