Objective: To define the epidemiology of broad-spectrum cephalosporin-resistant Gram-negative bacilli in intensive care units (ICUs) during a nonoutbreak period, including the prevalence, the risk factors for colonization, the frequency of acquisition, and the rate of infection. Design: Prospective cohort study, Setting: Tertiary care hospital. Patients: Consecutive patients admitted to two surgical ICUs. Main Outcome Measurements: Serial patient surveillance cultures screened for ceftazidime (CAZ) resistance, antibiotic and hospital exposure, and infections. Results: Of the 333 patients enrolled, 60 (18%) were colonized with CAZ-resistant Gram-negative bacilli (CAZ-RGN) at admission. Clinical cultures detected CAZ-RGN in only 5% (3/60) of these patients. By using logistic regression, CAZ-RGN colonization was associated with duration of exposure to cefazolin (odds ratio, 10.3; p less than or equal to .006) and to broad-spectrum cephalosporins/penicillins (odds ratio, 2; p less than or equal to .03), Acute Physiology and Chronic Health Evaluation III(TM) score (Odds ratio, 1.2; p less than or equal to .008), and previous hospitalization (odds ratio, 3.1; p less than or equal to .006). Of the 100 patients who remained in the surgical ICU for greater than or equal to 3 days, 26% acquired a CAZ-RGN. Of the 14 infections caused by CAZ-RGN, 11 (79%) were attributable to the same species present in surveillance cultures at admission to the surgical ICU. Conclusions: Colonization with CAZ-RGN was common and was usually not recognized by clinical cultures. Most patients colonized or infected with CAZ-RGN had positive surveillance cultures at the time of admission to the surgical ICU, suggesting that acquisition frequently occurred in other wards and institutions, Patients exposed to first-generation cephalosporins, as well as broad-spectrum cephalosporins/penicillins, were at high risk of colonization with CAZ-RGN. Empirical treatment of nosocomial Gram-negative infections with broad-spectrum cephalosporins, especially in the critically ill patient, should be reconsidered.