A vaccine strain of live, attenuated Salmonella typhimurium induces profound immunosuppression in inoculated mice 7 days after injection. Immunosuppression to mitogens and inability to mount plaque-forming responses to sheep red blood cells occurs in spite of many parameters of upregulated macrophage function and protection against challenge with virulent Salmonella. Studies show that macrophage nitric oxide mediates the immunosuppression and presumably also the early-onset protective capacity of the vaccine. A model of "bystander lymphocyte autotoxicity" is presented to explain the mechanism of immunosuppression. The model proposes that Salmonella-activated macrophages generate nitric oxide which inactivates lymphocytes in the vicinity, so they become dysfunctional. Inhibition of nitric oxide by NG-monomethyl-L-arginine reverses immunosuppression. Evidence is presented that supports a relationship between the microbial burden in the spleen, the degree of nitric oxide produced, and the extent of immunosuppression. It is proposed that this model of microbial immunosuppression mediated by nitric oxide is generalizable for understanding immunosuppression and loss of delayed-type hypersensitivity induced by other microbes, such as Mycobacteria and measles virus. The model could account for anergy during mycobacterial infections, particularly when the burden of acid-fast bacilli is high, as well as loss of skin test reactivity to tuberculin during measles infection.