Catheter-related bloodstream infection (CRBSI) in critically ill surgical patients with prolonged intensive care unit (ICU) stays is associated with a significant increase in health care resource use. Prospective cohort study. Surgical ICU at a large tertiary care center. Critically ill surgical patients (N = 260) with projected surgical ICU length of stay greater than 3 days. Central venous catheters were cultured for clinical suspicion of infection. Increases in total hospital cost, ICU cost, hospital days, and ICU days attributable to CRBSI were estimated using multiple linear regression after adjusting for demographic factors and severity of illness (APACHE III [Apache Physiology and Chronic Health Evaluation III] score). The incidence of CRBSI per 1000 catheter-days was 3.6 episodes (95% confidence interval [CI], 2.1-5.8 episodes). Microbiologic isolates were Gram-positive bacteria in 75%, Gram-negative bacteria in 20%, and yeast in 5%. After adjusting for demographic factors and severity of disease, CRBSI was associated with an increase of $56 167 (95% CI, $11 523-$165 735; P =.001) (in 1998 dollars) in total hospital cost, an increase of $71 443 (95% CI, $11 960-$195 628; P<.001) in ICU cost, a 22-day increase in hospital length of stay, and a 20-day increase in ICU length of stay. For critically ill surgical patients, CRBSI is associated with a profound increase in resource use. Prevention, early diagnosis, and intervention for CRBSI might result in cost savings in this high-risk population.