We compared antimicrobial resistance phenotypes and pulsed-field gel electrophoresis (PFGE) subtypes of 1,028 human and 716 animal Salmonella enterica serotype Typhimurium isolates from Minnesota from 1997 to 2003. Overall, 29% of human isolates were multidrug resistant. Predominant phenotypes included resistance to ampicillin, chloramphenicol or kanamycin, streptomycin, sulfisoxazole, and tetracycline (ACSSuT or AKSSuT). Most human multidrug-resistant isolates belonged to PFGE clonal group A, characterized by ACSSuT resistance (64%), or clonal group B, characterized by AKSSuT resistance (19%). Most animal isolates were from cattle (n = 358) or swine (n = 251). Eighty-one percent were multidrug resistant; of these, 54% were at least resistance phenotype ACSSuT, and 43% were at least AKSSuT. More than 80% of multidrug-resistant isolates had a clonal group A or B subtype. Resistance to ceftriaxone and nalidixic acid increased, primarily among clonal group A/ACSSuT isolates. Clonal group B/AKSSuT isolates decreased over time. These data support the hypothesis that food animals are the primary reservoir of multidrug-resistant S. Typhimurium.