Lipopolysaccharides (LPS) of gram-negative bacilli are known to protect mice against unrelated bacterial infections and to be nonspecific mitogens of murine bone marrow-derived (B-) lymphocytes. For assessment of the role of these cells in the mechanism of LPS-induced resistance to infection with Klebsielia, various nontoxic mitogens were assayed. In contrast to LPS or lipid A, the nontoxic mitogens did not protect mice. Experiments were also performed with LPS in nude mice and in mice treated with immunosuppressants. Stimulation by LPS was decreased after administration of hydrocortisone or cyclophosphamide under conditions that inhibited the in vitro activation of lymphocytes by mitogens. Moreover, nude mice and mice treated with 6-mercaptopurine were more resistant to Klebsiella than were control mice.