Background. Salmonella 4,,12:i:-, a worldwide emerging pathogen that causes many food-borne outbreaks mostly attributed to pig and pig products, is expanding in the United States Methods. Whole-genome sequencing was applied to conduct multiple comparisons of 659 S. 4,,12:i:-and 325 Salmonella Typhimurium from different sources and locations (ie, the United States and Europe) to assess their genetic heterogeneity, with a focus on strains recovered from swine in the US Midwest. In addition, the presence of resistance genes and other virulence factors was detected and the antimicrobial resistance phenotypes of 50 and 22 isolates of livestock and human origin, respectively, was determined. Results. Te S. 4,5,12:i:-strains formed two main clades regardless of their source and geographic origin. Most (84%) of the US isolates recovered in 2014-2016, including those (48 of 51) recovered from swine in the US Midwest, were part of an emerging clade. In this clade, multiple genotypic resistance determinants were predominant, including resistance against ampicillin, streptomycin, sulfonamides, and tetracyclines. Phenotypic resistance to enrofloxacin (11 of 50) and cefiofur (9 of 50) was found in conjunction with the presence of plasmid-mediated resistance genes (qnrB19/qnrB2/qnrS1 and blaCMY-2/blaSHV-12, respectively). Higher similarity was also found between S. 4,,12:i:-from the emerging clade and S. Typhimurium from Europe than with S. Typhimurium from the United States. Conclusions. Salmonella 4,,12:i:-currently circulating in swine in the US Midwest are likely to be part of an emerging multidrug-resistant clade frst reported in Europe, and can carry plasmid-mediated resistance genes that may be transmitted horizontally to other bacteria, and thus may represent a public health concern.