Mice bearing plasmacytomas have a severely impaired ability to mount a primary immune response; T cells from these mice, however, appear by both in vivo and in vitro criteria to function normally. This unusual pattern of immunodeficiency appears to be mediated by a regulatory cell found in the spleens and peritoneal cavities but not in the lymph nodes or thymuses of mice bearing plasmacytomas. The number of cells with suppressor activity in the spleens of plasmacytoma-bearing mice is directly proportional to the size of the subcutaneous tumor borne by the host. These cells are capable of suppressing antibody production in in vitro cultures of normal spleen cells but have no demonstrable effect on the ability of normal spleen cells to proliferate in vitro in response to phytohemagglutinin or 8-Br-guanosine-3', 5'-monophosphate (T and B cell mitogens, respectively). Characterization of the suppressor cell population on the basis of its cell surface properties, its radioresistance, its morphology, and its ability to adhere to various solid matrices suggest that these cells are adherent mononuclear cells. These data support the concept that plasma cell tumors indirectly induce an impairment in the humoral immune response of their hosts by stimulating the expression of regulatory functions in a population of splenic and peritoneal macrophages.