The outer membrane protein (OMP) preparation of Salmonella typhi was observed to have several immunomodulatory properties. Treatment of mice with an intraperitoneal injection of the OMP preparation enhanced both cellular and humoral responses of the mice to an unrelated antigen, a killed vaccine of Mycobacterium vaccae; both the delayed-type hypersensitivity (DTH) response and the antibody titers were enhanced. The predominant isotype of the antibody shifted from immunoglobulin G1 (IgG1) to IgG2a upon treatment with OMP. Treatment of mice with the OMP preparation improved the efficiency of in vitro antigen presentation by the peritoneal cells and also induced the cells to secrete interleukin-1. Treatment with the lipopolysaccharide (LPS) preparation of S. typhi had the opposite effect; i.e., the DTH response to M. vaccae was suppressed. Treatment with OMP neutralized the suppressive effects of LPS. The OMP preparation also had an enhancing effect on the innate immune mechanisms of the mice. Intraperitoneal injection of the OMP preparation enhanced the microbicidal activity of the peritoneal cells, and production of nitric oxide intermediates was stimulated. Injection of the OMP preparation into footpads of naive nonimmune mice induced a sustained hypersensitivity response that peaked at 24 h. Purified porins of the OMP preparation could induce both immunomodulation and hypersensitivity. Porins prepared from five different Salmonella strains and a strain of normal fecal Escherichia coli also exhibited immunomodulatory and hypersensitivity-inducing activities.