OBJECTIVE To evaluate the safety and efficacy of avirulent live Salmonella choleraesuis strain 54 (SC54) as a vaccine to protect calves against salmonellosis caused by S dublin. METHODS 40 head of clinically normal 3 to 5-week-old male Holstein calves that were culture negative for Salmonella sp. METHODS Calves were randomly assigned to 4 test groups of 10 calves each. Group 1 received 8.5 x 10(7) colony-forming units (CFU) of SC54 SC. Groups 2 and 3 received 1.13 x 10(9) CFU of SC54, SC and intranasally, respectively. Group 4 received saline solution as a vaccine control. All calves were challenge exposed orally with 1.74 x 10(9) CFU of virulent S dublin 14 days after vaccination. Clinical signs and Salmonella shedding were monitored for 28 days after vaccination. Calves were necropsied, and organs were cultured for Salmonella sp 14 days after challenge exposure. RESULTS Calves of groups 2 and 3 had slightly high rectal temperature after vaccination. Salmonella dublin challenge exposure resulted in mild clinical signs of salmonellosis. All vaccinated groups had significantly (P < 0.05) lower rectal temperature, fecal shedding of S dublin, and recovery of S dublin from organs after necropsy. SC54 was not recovered from fecal or blood samples collected after vaccination or from injection site samples or organs collected at necropsy. CONCLUSIONS SC54 given intranasally or SC to calves was safe and significantly (P < 0.05) reduced clinical signs and bacterial shedding after oral challenge exposure with S dublin. CONCLUSIONS SC54 has potential as an effective vaccine to aid in prevention of salmonellosis caused by S dublin in calves.