BACKGROUND. Catheter-related bloodstream infections (CRBSIs) account for the majority of hemodialysis-related infections. There are no published data on the efficacy of the chlorhexidine-impregnated foam dressing at reducing the rate of CRBSI among patients undergoing hemodialysis. DESIGN. A prospective, nonblinded, crossover intervention trial to determine the efficacy of a chlorhexidine-impregnated foam dressing to reduce the rate of CRBSI among patients undergoing hemodialysis. SETTING. Two outpatient dialysis centers. PATIENTS. A total of 121 patients who underwent dialysis through tunneled central venous catheters received the intervention during the trial. METHODS. The primary outcome of interest was the incidence of CRBSI. A nested cohort study of all patients who received the chlorhexidine-impregnated foam dressing was also conducted. Backward stepwise logistic regression analysis was used to determine independent risk factors for development of CRBSI. RESULTS. Thirty-seven CRBSIs occurred in the intervention group, for an incidence of 6.3 CRBSIs per 1,000 dialysis sessions, and 30 CRBSIs occurred in the control group, an incidence of 5.2 CRBSIs per 1,000 dialysis sessions (risk ratio, 1.22 [95% confidence interval [CI], 0.75-1.97]; P = .46). The chlorhexidine-impregnated foam dressing was well tolerated, with only 2 patients (<2%) experiencing dermatitis that led to its discontinuation. The only independent risk factor for development of CRBSI was dialysis treatment at one dialysis center (adjusted odds ratio, 4.4 [95% CI, 1.77-13.65]; P = .002). Age of at least 60 years (adjusted odds ratio, 0.28 [95% CI, 0.09-0.82]; P = .02) was associated with lower risk of CRBSI. CONCLUSIONS. The use of a chlorhexidine-impregnated foam dressing did not decrease the incidence of CRBSI among patients with tunneled central venous catheters who were undergoing hemodialysis.