This study characterizes the clinical response and colonization pattern of caesarean-derived, colostrum-deprived swine exposed to a DELTA-cya/DELTA-crp mutant (chi-4233) of S. typhimurium and challenged with the wild-type parent strain. Chi-4233 was mildly virulent in swine and induced transient fever and soft stools. Chi-4233 colonized the ileum, cecum, liver, spleen, tonsils, and mandibular and ileocolic lymph nodes of swine in a manner similar to the parental wild-type, but the numbers of S. typhimurium (chi-4233) in the ileum were 100- to 1000-fold less than those of pigs exposed to the parental wild-type. Pigs exposed to chi-4233 21 days before parental wild-type challenge demonstrated a milder clinical response to challenge than did pigs that did not receive chi-4233. The wild-type populations in the ilea of chi-4233-exposed pigs after challenge were 100- to 10,000-fold less than those in pigs not receiving chi-4233. The liver, spleen, and ileocolic lymph nodes were cleared of wild-type S. typhimurium more quickly after challenge in chi-4233-exposed pigs. The populations of chi-4233 in the ilea of exposed pigs after wild-type challenge were also less than would have been expected in unchallenged pigs. Thus, exposure of swine to a DELTA-cya/DELTA-crp mutant of S. typhimurium modulated the subsequent response to parental wild-type challenge and reduced carrier populations of wild-type S. typhimurium in infected swine.