Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli have emerged as significant causes of community-onset disease. We sought to identify risk factors for acquiring community-onset ESBL-producing E. coli.Prospective, population-based surveillance for ESBL-producing E. coli was performed in the Calgary Health Region (population 1.2 million), Canada during a two-year period.247 patients were identified; 177 (72%; 7.6 per 100,000/year) were community acquired, and 70 (28%; 3.0 per 100,000/year) were healthcare associated. The acquisition risk increased with advancing age. Females were at higher risk as compared to males [relative risk (RR) 4.3; 95% confidence interval (CI), 3.1–6.1] as were urban as compared to rural residents (RR 2.2; 95% CI, 1.4–3.6). A number of co-morbidities increased risk (RR; 95% CI) including requirement for hemodialysis (56.3; 15.1–147.4), urinary incontinence (21.7; 15.0–30.9), cancer (11.1; 7.0–17.0), heart disease (6.5; 4.3–9.7), and diabetes (4.4; 2.6–7.1). Overseas travel overall increased the risk (5.7; 4.1–7.8) and was highest in travelers to India (145.6; 77.7–252.1), the Middle East (18.1; 8.1–35.2), and Africa (7.7; 2.8–17.2).Advancing age, female gender, co-morbid medical conditions, and foreign travel are important risk factors for developing community-onset ESBL-producing E. coli infections in our region. Emergence of anti-microbial-resistant pathogens is a global concern.