Summary: Genetically altered stable nonreverting aromatic-dependent (aro-) Salmonella dublin, strain SL5631, was administered orally to healthy colostrum-fed calves as vaccine. Twenty-six calves were allotted to 4 groups. There were 2 experiments, each with a vaccinated and nonvaccinated control group. Skin testing with 0.1 ml of sonicated S dublin was performed 3 days prior to challenge exposure. The IgG and IgM titers to S dublin lipopolysaccharide (lps) antigen were determined by elisa on sera before initial vaccination and at 1.5 to 2 weeks after each vaccination. In experiment 1, six calves received a dose of 1.7 × 1010 colony-forming units (cfu) of aro-S dublin SL5631 orally at 2 and 4 weeks of age. After the first vaccination, 2 of 6 calves developed fever, but all 6 calves continued to have normal appetite and mental attitude. Adverse changes were not observed after the second vaccination. At the time of challenge exposure at 6 weeks of age, all 12 calves were seronegative for IgG and IgM lps-specific antibodies, and the difference in percentage increase in skin test reaction at 48 hours was not significant. At 6 weeks of age, the 6 vaccinates and 6 controls were orally challenge-exposed with 1.5 × 1011 cfu of virulent S dublin T2340. Protection from challenge was not evident, as 3 of 6 controls and 5 of 6 vaccinates died after challenge exposure. In experiment 2, eight calves received a dose of 5 × 1011 cfu of aro-S dublin SL5631 orally at 2, 3.5, and 5 weeks of age. The vaccine dose and volume (300 ml) were 30 times that of experiment 1. After each vaccination, some calves (7, 6, and 2 calves for first, second, and third doses, respectively) developed fever, but all calves continued to have normal appetite and attitude. At 7 weeks of age, the 8 vaccinates and 6 controls were orally challenge-exposed with 1.5 × 1011 cfu of virulent S dublin T2340 (same dose as experiment 1). At the time of challenge exposure, all 8 vaccinated calves had elisa titers to IgG and IgM lps-specific antibodies significantly above those of nonvaccinated calves (P < 0.01 and P < 0.05, respectively), 5 of 8 had a strongly posisitive skin test reaction to lps, and the group mean percentage increase in skin thickness 48 hours after intradermal injection was 135% (P = 0.01). The 6 control calves had negative elisa results and mean increase in skin thickness of 34%. Protection from challenge exposure was evident as vaccinates remained blood culture-negative, whereas 5 of 6 controls were blood culture-positive; vaccinates did not develop diarrhea, whereas all controls developed diarrhea. All vaccinates survived, but 3 of 6 controls died after challenge exposure (P = 0.05). Failure of orally administered vaccine to protect calves in experiment 1 appeared attributable to insufficient antigenic stimulation when 1.7 × 1010 cfu of aro−S dublin SL5631 was administered. In experiment 2, a larger number of vaccinal organisms given orally was able to induce a measurable systemic immune response and protection, but the vaccine volume makes it unlikely to be practical for field use.