Monoclonal antibodies (MAbs) were raised against the outer membrane (OM) antigens of Salmonella typhimurium. Enzyme-linked immunosorbent assays and Western immunoblots indicated that 10 MAbs in the panel were specific for surface epitopes, and 10 recognized buried epitopes of OmpC or OmpD porins; three MAbs reacted with smooth lipopolysaccharide (LPS), two bound rough LPS, and the remaining three MAbs apparently reacted with a porin-LPS complex. We screened these MAbs and immune polyclonal sera in CAF1 (Ity(r)) mice for their relative immunoprotective potential against a challenge with 10 to 500 LD50 of the virulent S. typhimurium LT-2 strain WB600, or against two LD50 of purified OM from this organism. Polyclonal sera that contained high titers of antibodies to porin monomers and trimers, and LPS, provided significant protection (33 to 100% survivors). Antiporin MAbs, when administered individually, did not protect or prolong the survival of mice. A mixture of MAbs with specificity for the surface, but not buried epitopes of porins, prolonged the survival of mice against endotoxemia, but none provided significant protection against mouse typhoid. MAbs specific for smooth (but not rough) LPS on the other hand, conferred significant protection against endotoxemia and mouse typhoid. Finally, MAbs that presumably recognized epitopes present in porin-LPS complexes, were also protective against endotoxemia and mouse typhoid. These results support the role of antibodies to LPS O-chains, porin-LPS complexes, and to a lesser degree, native porins in acquired resistance to infection by S. typhimurium.