Objective. To identify predictors of community-onset extended-spectrum β-lactamase (ESBL)-producing Escherichia coli infection. design. Prospective case-control study. Setting. Acute care hospitals and ambulatory clinics in the Chicago, Illinois, region. patients. Adults with E. coli clinical isolates cultured in ambulatory settings or within 48 hours of hospital admission. methods. Cases were patients with ESBL-producing E. coli clinical isolates cultured in ambulatory settings or within 48 hours of admission, and controls were patients with non-ESBL-producing E. coli isolates, matched to cases by specimen, location, and date. Clinical variables were ascertained through interviews and medical record review. Molecular methods were used to identify ESBL types, sequence type ST131, and aac(6')-Ib-cr. results. We enrolled 94 cases and 158 controls. Multivariate risk factors for ESBL-producing E. coli infection included travel to India in the past year (odds ratio [OR], 14.40 [95% confidence interval (CI), 2.92-70.95]), ciprofloxacin use (OR, 3.92 [95% CI, 1.90-8.1]), and age (OR, 1.04 [95% CI, 1.02-1.06]). Case isolates exhibited high prevalence of CTX-M-15 (78%), ST131 (50%), and aac(6′)-Ib-cr (66% of isolates with CTX-M-15 conclusions. Providers should be aware of the increased risk of ESBL-producing E. coli infection among returned travelers, especially those from India.