Background: Extended-spectrum β-lactamase (ESBL)-producing organisms, first identified in Germany in 1983, are now widely recognized as clinically relevant causes of infections in community. Methods: Our objective was to evaluate the clinical and molecular epidemiology of community-onset, extended-spectrum β-lactamase (CO-ESBL)-producing Escherichia coli infections. We used a case-case-control study undertaken in a 450-bed, tertiary care hospital. Patients included case group (CG) I, which had confirmed CO-ESBL-producing E coli infections (n = 46). Case group (CG) II (n = 46) included patients with CO-non-ESBL-producing E coli infections. Controls (n = 138) were patients without infections. Results: By multivariate analysis, diabetes (95% confidence interval [CI]: 1.9-13.2, P < .001), prior ESBL E coli colonization (<90 days) (95% CI: 1.2-67.8, P < .001), recent receipt of antibiotics (<90 days) (95% CI: 4.2-44.2, P = .004), and previous exposure to third-generation cephalosporins (95% CI: 2.2-16.4, P = .001) and fluoroquinolones (95% CI: 1.4-18.3; P = .003) were associated risks among CG I. Diabetes (95% CI: 1.6-15.4, P = .005), stroke (95% CI: 1.5-17.1, P = .001), and diarrhea (95% CI: 3.8-65.8, P = .001) were risks among CG II. Patients with CO-ESBL in CG I versus controls were more likely to die (30% vs 0%, respectively; P < .001), had prolonged hospital length of stay (8 vs 5 days, respectively; P < .001), and had higher hospitalization costs (median, US $528 vs $108, respectively; P < .001). The plasmid carrying the CTX-M-15 gene was identified in 13 of 25 (52%) available CO-ESBL-producing E coli isolates. Conclusion: CO-ESBL-producing E coli is an emerging multidrug-resistant microorganism in Thailand. Patients with prior ESBL colonization and recent antibiotic exposures, especially to third-generation cephalosporins and fluoroquinolones, were at risk for CO-ESBL-producing E coli infection.