Reports of
Salmonella
enterica
I serotype 4,[5],12:i:- infections resistant to ampicillin, streptomycin, sulphamethoxazole, and tetracycline (ASSuT) have been increasing. We analyzed data from 5 national surveillance systems to describe the epidemiology, resistance traits, and genetics of infections with this
Salmonella
strain in the United States. We found ASSuT-resistant
Salmonella
4,[5],12:i:- increased from 1.1% of
Salmonella
infections during 2009–2013 to 2.6% during 2014–2018; the proportion of
Salmonella
4,[5],12:i:- isolates without this resistance pattern declined from 3.1% to 2.4% during the same timeframe. Among isolates sequenced during 2015–2018, a total of 69% were in the same phylogenetic clade. Within that clade, 77% of isolates had genetic determinants of ASSuT resistance, and 16% had genetic determinants of decreased susceptibility to ciprofloxacin, ceftriaxone, or azithromycin. Among outbreaks related to the multidrug-resistant clade, 63% were associated with pork consumption or contact with swine. Preventing
Salmonella
4,[5],12:i:- carriage in swine would likely avert human infections with this strain.