CD200 is an immunoregulatory protein, highly expressed on activated T and B cells and on various liquid and solid tumors. We have previously shown that treatment with an antagonist anti-CD200 antibody in vivo enhances anti-tumor immunity in a hematologic cancer model. The present studies evaluated whether in vivo anti-CD200 treatment modulates hematopoietic cell subsets and allo- and auto- antibody responses in an AIHD model. Mice were immunized weekly with rat red blood cells (RBC) to prompt robust anti-rat RBC allo- and cross-reactive auto- antibody responses. Immunized mice were randomized into groups receiving either vehicle alone, an anti-CD200 antibody (OX90mG2a), a non-reactive, isotype-matched control antibody (12B4mG2a), cyclosporine (CsA), or CsA plus OX90mG2a or 12B4G2a antibodies. Allo- and auto- antibodies were measured prior to and at the conclusion of treatment. Administration of OX90mG2a with or without CsA significantly impacted CD200+ cell subsets in treated mice. Decreased frequencies of CD200+ T cells, B cells, plasma cells and progenitor bone marrow cells were observed in OX90mG2a-treated mice relative to control mice. All CD200+ populations returned to normal levels after termination of anti-CD200 treatment. OX90mG2a administration also inhibited allo- and auto- antibody production in this model. These data suggest that anti-CD200 antibody therapy is a potent immunomodulator and may provide a therapeutic strategy for antibody-mediated diseases.