Immunotherapy using Rituximab, an unconjugated CD20 monoclonal antibody, has proven effective for treating non-Hodgkin’s lymphoma and autoimmune disease. CD19 antibody immunotherapy is also effective in mouse models of lymphoma and autoimmunity. In both cases, mouse models have demonstrated that effector cell networks effectively deplete the vast majority of circulating and tissue B lymphocytes through Fcγ receptor-dependent pathways. In mice, B cell depletion is predominantly, if not exclusively, mediated by monocytes. CD20 mAbs rapidly deplete circulating and tissue B cells in an antibody isotype-restricted manner with a hierarchy of antibody effectiveness: IgG2a/c > IgG1 > IgG2b >> IgG3. Depending on antibody isotype, mouse B cell depletion is regulated by FcγRI-, FcγRII-, FcγRIII-, and FcγRIV-dependent pathways. The potency of IgG2a/c mAbs for B cell depletion in vivo results from FcγRIV interactions, with likely contributions from high-affinity FcγRI. IgG1 mAbs induce B cell depletion through preferential, if not exclusive, interactions with low-affinity FcγRIII, while IgG2b mAbs interact preferentially with intermediate-affinity FcγRIV. By contrast, inhibitory FcγRIIB-deficiency significantly increases CD20 mAb-induced B cell depletion at low mAb doses by enhancing monocyte function. Thus, isotype-specific mAb interactions with distinct FcγRs contribute significantly to the effectiveness of CD20 mAbs in vivo. These results provide a molecular basis for earlier observations that human FcγRII and FcγRIII polymorphisms correlate with the in vivo effectiveness of CD20 antibody therapy. That the innate monocyte network depletes B cells through FcγR-dependent pathways during immunotherapy has important clinical implications for CD19, CD20, and other antibody-based therapies for the treatment of diverse B cell malignancies and autoimmune disease.