Salmonella serotype I 4,,12:i:- has emerged as a leading cause of human disease, both in Europe and the United States. Data from swine diagnostic samples submitted to the Iowa State University Veterinary Diagnostic Laboratory (ISU-VDL) reveals a substantial increase in the relative frequency of isolation of this serotype from <3% in 2011 to >15% of all Salmonella isolated in 2015. While Salmonella Typhimurium is a primary enteric pathogen of swine, most serotypes are considered to be less pathogenic and can be isolated from otherwise healthy pigs (such as Derby). In a review of case data from clinical submissions to the ISU-VDL, there is a consistent association between enteric disease with concurrent histologic lesions compatible with salmonellosis and isolation of I 4,,12:i:-. Between January 1, 2016 and March 23, 2016, compatible histologic lesions of salmonellosis were confirmed in 39 of 51 cases from which 4, , 12:i:- was isolated, and in 17 of 18 and 1 of 7 cases in which Typhimurium or Derby, respectively, were isolated. Antibiotic susceptibility testing data on the ISU-VDL swine isolates of I 4,,12:i- confirms a rapid increase in the identification of ASSuT (ampicillin, streptomycin, sulfonamide and tetracycline) multi-drug resistant isolates (from 3.5% in 2012 to 36.8% of isolates identified thus far in 2016). In comparison, the percentage of Typhimurium isolates exhibiting the same resistance profile has remained relatively steady at approximately 10-11% since 2007. Importantly, 11 of 663 isolates of I 4,,12:i:- had resistance to all antibiotic classes tested (beta-lactams, cephalosporins, pleuromutilins, tetracyclines, aminoglycosides, amphenicols, fluoroquinolones, lincosomides, macrolides, and folate pathway inhibitors). In contrast, no isolates of Typhimurium with this profile have been identified to date. The increased isolation of I 4,,12:i:- in association with clinical disease in swine along with increasing identification of the ASSuT MDR resistance profile in this serotype warrants increased awareness.