A heavy-chain class-specific, solid-phase radioimmunoassay was developed to characterize the murine antibody response to Salmonella typhimurium. The specificity of the assay was verified by quantitation of the extent of binding of anti-S. typhimurium antibodies to other bacterial genera and species and by cross-adsorption studies. The sensitivity of the procedure was also examined, and it was determined to be substantially more sensitive than either the passive hemagglutination or the whole-cell agglutination technique. The method was subsequently used to analyze th murine antibody response to S. typhimurium. Groups of mice were prebled and then immunized with live S. typhimurium via different routes. The animals were bled weekly for 12 weeks, and then sera were assayed for antibodies directed against whole bacteria or purified lipopolysaccharide. Anti-Salmonella antibodies of the immunoglobulin M class appeared in the serum approximately 2 to 3 weeks after immunization, and then immunoglobulin G anti-Salmonella antibodies appeared which constituted the major part of the long-term response. Immunoglobulin A was not a major component of the serum antibody response. The antibodies were primarily directed against the lipopolysaccharide determinants, but a small percentage of the response was directed against other cell surface components. Qualitatively and quantitatively similar anti-Salmonella antibody responses were observed in sera of outbred and inbred strains of mice.