Infections are frequently associated with immunosuppressive therapy currently used to prevent organ rejection or treat autoimmune diseases. Such drugs suppress antibody production despite having different mechanisms of action. Antibodies are produced by a non-homogenous population of B lymphocyte subsets. B-1 cells produce natural antibodies and protect immediately after infection, while B2 cells produce antigen-specific IgM antibodies in a later response to infection. To understand how the immunosuppressive drugs affect antibody production by B cell populations, we immunized BALB/c mice with different antigens followed by administration of various immunosuppressive drugs. B-1a and B-1b lymphocytes from spleens of sacrificed animals were analyzed by flow cytometry, natural and antigen -specific IgG and IgM antibodies were determined by nephelometry and ELISA assays. Results showed that prednisone (PDN), cyclophosphamide (CYC), methotrexate (MTX), mycophenolate mofetil (MMF) and azathioprine (AZA) decreased more than 60% of B-1a lymphocytes while cyclosporine (CsA) had little effect. Three drugs PDN, AZA and CYC suppressed the B-2 cells on day 30, while MTX affected this subpopulation early on day 5. Antigen-specific IgM antibodies were dramatically suppressed after 15 days of immunization in animals receiving PDN, CYC or AZA, while MMF, CsA and MTX showed little effect. Natural antibodies were equally decreased in all animals regardless of the specific drug used in treatment. These results will help to choose single or combinations of immunosuppressive drugs in the clinical setting.