Objective--To evaluate effects of a Salmonella Newport siderophore receptor and porin protein (SRP) vaccine on cattle health and performance and on prevalence of fecal shedding of Salmonella bacteria in feedlot cattle. Animals--1,591 beef cattle. Procedures--Cattle were randomly allocated within a replicate (n = 10 replicates [20 total pens]), administered 2 mL of a Salmonella Newport SRP vaccine (n = 795 cattle) or a placebo (796), and revaccinated approximately 21 days after the first administration. Health and performance data were recorded by trained feedlot personnel who were blinded to treatment. Fresh fecal samples (n = 25) were collected from pen floors on days 0, 60, and 120 and within 24 hours of cattle harvest and were subjected to selective Salmonella culture and serotyping by laboratory personnel who were blinded to treatment. Pen-level mixed models were used to analyze data. Results--Significant differences in fecal prevalence of Salmonella bacteria or health and performance variables were not detected between vaccinated and control cattle. Salmonella bacteria were recovered from all 10 replicates, and cumulative prevalence estimates ranged from 1.5% to 22%. Overall prevalence of fecal shedding of Salmonella bacteria was 10.2% and 10.9% in vaccinated and control cattle, respectively. Overall morbidity risk was 34.8% for both vaccinated and control cattle. Overall mortality risks were 1.9% and 1.1% for vaccinated and control cattle, respectively. Conclusions and Clinical Relevance--In this setting, administration of the Salmonella Newport SRP vaccine in feedlot cattle had no effect on fecal prevalence of Salmonella bacteria or cattle health and performance.