A prospective, population-based laboratory surveillance study was conducted to define the epidemiology of extended-spectrum β-lactamase-producing Escherichia coli infections in the Calgary Health Region during the years 2000–2002. The incidence was 5.5 cases per 100,000 population per year. The annualized incidence of 3.9 cases per 100,000 population for January through March was significantly lower than the incidence for the other quarters of the year (6.0 per 100,000 population; P < .01). Seventy-one percent of subjects had community-onset disease. Patients aged ≥65 years (22.0 vs. 3.8 cases per 100,000 population per year; P < .0001) and women (9.2 vs. 1.7 cases per 100,000 population per year; P < .0001) had significantly higher rates of infection. Polymerase chain reaction identified 23 (15%) of 157 isolates as positive for blaCTX-M genes from the CTX-M-I subgroup and 87 (55%) from the CTX-M-III subgroup. Ciprofloxacin resistance was independently associated with CTX-M-β-lactamases (odds ratio, 14.2; 95% confidence interval, 3.69–54.84). Strains of E. coli with blaCTX-M genes commonly cause community-onset infections, and women and older patients are at highest risk.