The present study advances our knowledge of the newly described immunodeficient RIII AnN mouse. This strain was found to have markedly reduced spleen size and low serum levels of IgM, IgA, IgG1, IgG2α, and IgG2β. Studies of F2 and backcross mice demonstrated that the defective immunoglobulin production was due to multiple genes: a dominant gene for low IgA and recessive genes for the others. RIII mice, like xid-bearing mice, had a markedly reduced splenic plaque-forming cell (PFC) response to Type III pneumococcal polysaccharide; however, unlike xid-bearing mice, the RIII AnN mice produced substantial serum antibody responses to pneumococcal polysaccharide, polyriboinosinic · polyribocytidylic acid, and trinitrophenyl-Ficoll. In addition, spleen cells from RIII AnN mice proliferated normally when stimulated with anti-μ, whereas those from xid mice did not. Thus, RIII AnN mice represent a model of hypogamma-globulinemia and restricted immunodeficiency. They differ from other immunodeficient mice, and should assist in the analysis of immunodeficiency, autoimmunity, and regulation of class-specific immunoglobulin production. © 1984.