To assess the contributions of bacterial virulence factors and defects in host defense to Escherichia coli bacteremia, we examined isolates and available medical records from 169 episodes at two hospitals. Adhesins and hemolysin virulence factors were documented in 84% of bacteremia-associated isolates originating from the urinary and respiratory tracts and in 50% of such isolates originating from other extraurinary foci. Of the evaluable episodes of bacteremia involving 35 adhesin-negative isolates, 21 (60%) were in patients who had mucocutaneous defects at the primary site of infection, and another 13 (37%) were in patients who had comorbid systemic diseases (i.e., chronic renal failure or alcoholism) associated with impaired leukocyte function. In contrast, of 93 evaluable episodes with adhesin-positive isolates, 22 (24%) were in patients who had none of these host conditions (P = .008). Overall, of evaluable episodes of bacteremia involving 128 isolates, 71 (55%) had both bacterial virulence-associated and host-related risk factors. Mortality was related to the severity of comorbid illnesses and was not affected by the presence of the bacterial virulence factors assessed.