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Background Despite the recent emergence of plasmid-mediated colistin resistance, the epidemiology and mechanisms of colistin-resistant Enterobacterales (CORE) infections remain poorly understood. Methods A case–case–control study was conducted utilizing routine clinical isolates obtained at a single tertiary health system in Ann Arbor, Michigan. Patients with CORE isolates from January 1, 2016, to March 31, 2017, were matched 1:1 with patients with colistin-susceptible Enterobacterales (COSE) and uninfected controls. Multivariable logistic regression was used to compare clinical and microbiologic features of patients with CORE and COSE to controls. A subset of available CORE isolates underwent whole-genome sequencing to identify putative colistin resistance genes. Results Of 16 373 tested clinical isolates, 166 (0.99%) were colistin-resistant, representing 103 unique patients. Among 103 CORE isolates, 103 COSE isolates, and 102 uninfected controls, antibiotic exposure in the antecedent 90 days and age >55 years were predictors of both CORE and COSE. Of 33 isolates that underwent whole-genome sequencing, a large variety of mutations associated with colistin resistance were identified, including 4 mcr -1/ mcr -1.1 genes and 4 pmrA/B mutations among 9 Escherichia coli isolates and 5 mgrB and 3 PmrA mutations among 8 Klebsiella pneumoniae isolates. Genetic mutations found in Enterobacter species were not associated with known phenotypic colistin resistance. Conclusions Increased age and prior antibiotic receipt were associated with increased risk for patients with CORE and for patients with COSE. Mcr -1, pmrA/B , and mgrB were the predominant colistin resistance–associated mutations identified among E. coli and K. pneumoniae, respectively. Mechanisms of colistin resistance among Enterobacter species could not be determined. [ABSTRACT FROM AUTHOR]