The prevalence and diversity of multidrug-resistant (MDR) Salmonella enterica strains associated with cattle at harvest in the United States were examined. Hides and carcasses of cattle were sampled at processing plants (n ؍ 6) located in four geographically distant regions from July 2005 to April 2006. The mean prevalences of Salmonella on hides, preevisceration carcasses (immediately after hide removal), and postintervention carcasses (in the chiller and after the full complement of interventions) were 89.6%, 50.2%, and 0.8%, respectively. The values for MDR Salmonella enterica strains (defined as those resistant to two or more antimicrobials) as percentages of Salmonella prevalence were 16.7% (95% confidence interval [CI], 8.3 to 25.1%; median percent prevalence, 6.9%), 11.7% (95% CI, 4.4 to 19.0%; median, 4.8%), and 0.33% (95% CI, ؊0.3 to 0.70%; median, 0%), respectively. In this study, 16,218 Salmonella hide and carcass isolates were screened for antimicrobial resistance. Of these, 978 (6.0%) unique MDR S. enterica isolates were identified and serotyped and their XbaI pulsed-field gel electrophoresis (PFGE) profiles determined. The predominant MDR S. enterica serotypes observed were Newport (53.1%), Typhimurium (16.6%), and Uganda (10.9%). Differences in MDR S. enterica prevalence were detected, and PFGE analysis revealed both epidemic clusters (profiles found in plants in multiple regions/seasons) and endemic clusters (profiles observed in plants in limited regions/seasons) within several of the MDR serotypes examined. Despite these differences, multiple-hurdle processing interventions employed at all plants were found to be quite effective and decreased Salmonella carcass contamination by 98.4% (95% CI, 97.6 to 99.7%).