Escherichia coli ranks among the organisms most frequently isolated from cases of bacteremia. The relative contribution of the host and bacteria to E. coli bacteremia severity remains unknown. We conducted a prospective multicenter cohort study to identify host and bacterial factors associated with E. coli bacteremia severity. The primary endpoint was in-hospital death, up to 28 days after the first positive blood culture. Among 1,051 patients included, 136 (12.9%) died. Overall, 604 (57.5%) patients were female. The median age was 70 years, and 202 (19.2%) episodes were nosocomial. The most frequent comorbidities were immunocompromised status (37.9%), tobacco addiction (21.5%), and diabetes mellitus (20.1%). The most common portal of entry was the urinary tract (56.9%). Most E. coli isolates belonged to phylogenetic group B2 (52.0%). The multivariate analysis retained the following factors as predictive of death: older age (odds ratio [OR] = 1.25 [95% confidence interval {CI}, 1.09 to 1.43] for each 10-year increment), cirrhosis (OR = 4.85 [95% CI, 2.49 to 9.45]), hospitalization before bacteremia (OR = 4.13 [95% CI, 2.49 to 6.82]), being an immunocompromised patient not hospitalized before bacteremia (OR = 3.73 [95% CI, 2.25 to 6.18]), and a cutaneous portal of entry (OR = 6.45 [95% CI, 1.68 to 24.79]); a urinary tract portal of entry and the presence of the ireA virulence gene were negatively correlated with death (OR = 0.46 [95% CI, 0.30 to 0.70] and OR = 0.53 [95% CI, 0.30 to 0.91], respectively). In summary, host factors and the portal of entry outweigh bacterial determinants for predicting E. coli bacteremia severity.