Although Escherichia coli is the most common cause of bloodstream infection, its epidemiology has not been well defined in non-selected populations. We sought to describe the incidence of risk factors for, and outcomes associated with, E. coli bacteraemia. Population-based surveillance for E. coli bacteraemia was conducted in the Calgary Health Region (population 1.2 million) during the period 2000–2006. In total, 2368 episodes of E. coli bacteraemia were identified for an overall annual population incidence of 30.3/100 000; 15% were nosocomial, 32% were healthcare-associated community-onset and 53% were community-acquired bacteraemias. The very young and the elderly were at highest risk for E. coli bacteraemia. Sixty per cent of the episodes occurred in females (relative risk 1.5; 95% CI 1.4–1.6). Dialysis, solid organ transplantation and neoplastic disease were the most important risk factors for acquiring E. coli bacteraemia. Rates of resistance to ampicillin, trimethoprim–sulphamethoxazole, gentamicin, ciprofloxacin, cefazolin and ceftriaxone increased significantly during the period 2000–2006. The case-fatality rate was 11% and the annual population mortality rate was 2.9/100 000. Increasing age, ciprofloxacin resistance, non-urinary focus and a number of comorbid illnesses were independently associated with an increased risk of death, and community acquisition and urinary focus were associated with a lower risk of death. This study documents the major burden of illness associated with E. coli bacteraemia and identifies groups at increased risk for acquiring and dying from these infections. The emergence of ciprofloxacin resistance and its adverse effect on patient outcome is a major concern.