OBJECTIVE. To determine risk factors and outcomes associated with ciprofloxacin resistance in clinical bacterial isolates from intensive care unit ( ICU) patients. DESIGN. Prospective cohort study. SETTING. Twenty- bed medical- surgical ICU in a Canadian tertiary care teaching hospital. PATIENTS. All patients admitted to the ICU with a stay of at least 72 hours between January 1 and December 31, 2003. METHODS. Prospective surveillance to determine patient comorbidities, use of medical devices, nosocomial infections, use of antimicrobials, and outcomes. Characteristics of patients with a ciprofloxacin- resistant gram- negative bacterial organism were compared with characteristics of patients without these pathogens. RESULTS. Ciprofloxacin- resistant organisms were recovered from 20 ( 6%) of 338 ICU patients, representing 38 ( 21%) of 178 nonduplicate isolates of gram- negative bacilli. Forty- nine percent of Pseudomonas aeruginosa isolates and 29% of Escherichia coli isolates were resistant to ciprofloxacin. In a multivariate analysis, independent risk factors associated with the recovery of a ciprofloxacin- resistant organism included duration of prior treatment with ciprofloxacin ( relative risk [ RR], 1.15 per day [ 95% confidence interval {CI}, 1.08- 1.23]; P <.001), duration of prior treatment with levofloxacin ( RR, 1.39 per day [ 95% CI, 1.01- 1.91]; P=.04), and length of hospital stay prior to ICU admission ( RR, 1.02 per day [ 95% CI, 1.01- 1.03];). Neither ICU mortality ( 15% of patients with a ciprofloxacin- resistant Pp. 005 isolate vs 23% of patients with a ciprofloxacin- susceptible isolate;) nor in- hospital mortality ( 30% vs 34%;) were statistically Pp. 58 Pp. 81 significantly associated with ciprofloxacin resistance. CONCLUSIONS. ICU patients are at risk of developing infections due to ciprofloxacin- resistant organisms. Variables associated with ciprofloxacin resistance include prior use of fluoroquinolones and duration of hospitalization prior to ICU admission. Recognition of these risk factors may influence antibiotic treatment decisions.