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Abstract Introduction Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli infections have become endemic worldwide. We aimed to describe the molecular and clinical epidemiology of ESBL-producing E. coli infections during a period of rising global prevalence. Methods Three hundred sixty-nine consecutive ESBL-producing E. coli infections in Detroit from 2010–2011 were analyzed. Sequence typing (ST) and CH typing were performed. Clinical characteristics and outcomes were compared between patients infected with ST131 and non-ST131 isolates. Results Ninety-six percent of isolates were ST 131, and 78.6% of ST 131 isolates produced bla CTX-M-15. Median time to effective therapy was 48 h vs. 35 h (P = 0.38) in the ST131 vs. non-ST131 groups. Ninety-day mortality rates (8% vs. 8%, P = 1.0) were similar between the two groups. Conclusion bla CTX-M-15 ST131 E. coli predominated in Detroit during an early period of global ST131 dissemination. Patients with ST131 E. coli infections had similar clinical outcomes to those with non-ST131 E. coli infections.