Between January 1988 and December 1992, 35 episodes of Escherichia coli bacteremia were identified in a series of 230 cases of bacteremia in neutropenic patients with cancer. Thirteen episodes (37%) were due to quinolone-resistant strains. Minimal inhibitory concentrations of norfloxacin ranged from 16 micrograms/mL to 128 micrograms/mL, and those of ciprofloxacin from 8 micrograms/mL to 64 micrograms/mL. The incidence of bacteremia due to quinolone-resistant E. coli increased from zero episodes per 1,000 hospital admissions in 1988 to four episodes per 1,000 admissions in 1992 (P = .018). To identify risk factors for quinolone-resistant E. coli bacteremia, we compared episodes of quinolone-resistant and quinolone-susceptible E. coli bacteremia. Among the variables analyzed, prophylaxis with norfloxacin was the only factor significantly associated with the development of quinolone-resistant E. coli bacteremia; 13 of 13 patients with bacteremia due to resistant strains received norfloxacin, whereas only one (5%) of 22 patients with bacteremia due to susceptible strains did (P < .001). According to our data, neutropenic patients with cancer who receive fluoroquinolone prophylaxis may be at risk of developing E. coli bacteremia due to quinolone-resistant strains.