We describe a field investigation in New England that identified the emergence and epidemiology of new strains of multidrug-resistant Salmonella, Newport-MDRAmpC, and summarize the Center for Disease Control and Prevention's surveillance data for these infections. In Massachusetts, the prevalence of Newport-MDRAmpC among Salmonella serotype Newport isolates obtained from humans increased from 0% (0/14) in 1998 to 53% (32/60) in 2001 (P<.001). In a retrospective case-control study, infection with Newport-MDRAmpC was domestically acquired and was associated with exposure to a dairy farm. Isolates from both humans and cattle had indistinguishable or closely related antibiograms and pulsed-field gel electrophoresis patterns. Nationally, the prevalence of ceftriaxone-resistant Salmonella increased from 0.5% in 1998 to 2.4% in 2001; 85% of the isolates in 2001 were Newport-MDRAmpC, and at least 27 states have isolated these strains from humans, cattle, or ground beef. These data document the widespread emergence of Newport-MDRAmpC strains in the United States and show that the 5-fold increase in the prevalence of Salmonella resistant to expanded-spectrum cephalosporins, between 1998 and 2001, is primarily due to the emergence of Newport-MDRAmpC strains.