Food borne Salmonella Typhimurium is a valid concern for the global pork industry. An attenuated oral swine Salmonella Choleraesuis vaccine has proven to be an effective tool for the pre-harvest reduction of carrier rates for multiple Salmonella spp. Serum antibody assays are available to monitor exposure to wild-type Salmonella infection. This clinical study assessed protection induced by an attenuated oral Salmonella Choleraesuis vaccine against challenge infection with S. Typhimurium in swine. A serologic antibody assay was concurrently evaluated for its ability to differentiate vaccinated pigs from those challenged with Salmonella Typhimurium. Vaccination significantly improved clinical scores, pyrexia, and enteric lesion prevalence, while numerically improving average daily weight gain, and group body weight variation in comparison to unvaccinated/challenged pigs. Vaccination, while protecting pigs against disease, did not generate detectable serum antibodies prior to challenge. No vaccinated animals became seropositive prior to challenge, indicating that conventional ELISA tests could be used in vaccinated pigs to monitor wild-type exposure. Following challenge, there was no detectable difference between vaccinated/challenged and non-vaccinated/challenged animals. All strict control pigs remained serum antibody negative. These findings support the use of this vaccine to protect swine against S. Typhimurium, without confounding pre-harvest Salmonella serologic monitoring programs.