BACKGROUND:: There are limited data on fluoroquinolone resistance and its impact on mortality in cases of Escherichia coli bloodstream infection (BSI). OBJECTIVE:: To determine risk factors for in-hospital mortality among patients with E coli BSIs. DESIGN:: A retrospective case-control study. SETTING:: A 1250-bed tertiary academic medical center. PATIENTS:: Patients with fluoroquinolone-resistant E coli BSI from January 1, 2000 through December 31, 2005 with 1:1 matched control patients with fluoroquinolone-sensitive E coli BSI. INDEPENDENT OUTCOME:: In-hospital mortality. RESULTS:: A total of 93 cases and 93 control patients were included. Compared with control patients, cases were more likely to be admitted from a long-term care facility (35% vs. 9%; P <.001) and to have a hospital-acquired bacteremia (54% vs. 33%; P =.008). Crude mortality was 26% for cases and 8% for controls (P =.002). On univariate analysis, predictors for in-hospital mortality included female gender, admission from a long-term care facility, APACHE II score >10, Charlson comorbidity score >4, cardiac dysfunction, cirrhosis, renal dysfunction, treatment with corticosteroids, and a fluoroquinolone-resistant E coli bacteremia. On multivariate analysis, independent risk factors for in-hospital mortality were cirrhosis (adjusted odds ratio [aOR], 7.2; confidence interval [CI], 1.7-29.8; P =.007), cardiac dysfunction (aOR, 3.9; CI, 1.6-9.4; P =.003), and infection with a fluoroquinolone-resistant E coli isolate (aOR, 3.9; CI, 1.5-10.2; P =.005). CONCLUSIONS:: After controlling for severity of illness and multiple comorbidities only fluoroquinolone resistance, cirrhosis, and cardiac dysfunction independently predicted mortality in patients with E coli bacteremia.