OBJECTIVES: To compare the costs with the benefits of using chlorhexidine digluconate dressings on central venous catheters and to determine the effectiveness of these dressings in reducing local infections and catheter-related bloodstream infections (CRBSIs), costs, and mortality. DESIGN: Cost-benefit analysis using randomized, controlled trial data on chlorhexidine digluconate dressing prevention of local infection and CRBSI, data on cost of chlorhexidine digluconate dressing versus standard treatment, data on averted cost of treating local infection and CRBSI, and data on mortality attributable to CRBSI. Decision analysis evaluated averted CRBSI treatment cost per patient resulting from chlorhexidine digluconate dressing use. Sensitivity analyses demonstrated net benefit of chlorhexidine  digluconate dressing, varying baseline rate of CRBSI, incremental cost of treating CRBSI, and number of catheters, and evaluated mortality preventable through chlorhexidine digluconate dressing use, varying baseline rate of CRBSI, number of catheters, and mortality attributable to CRBSI. PATIENTS AND SETTING: Patients of all Philadelphia area hospitals and one Philadelphia academic medical center. RESULTS: Estimated potential annual U.S. net benefits from chlorhexidine digluconate dressing use ranged from US Dollars 275 million to approximately US Dollars 1.97 billion. Cost-benefit findings persisted in sensitivity analyses varying baseline rate of CRBSI, incremental cost of treating CRBSI, and overall number of catheters used. Preventable mortality analyses showed potential decreases of between 329 and 3,906 U.S. deaths annually as a result of nationwide use of chlorhexidine digluconate dressing. CONCLUSIONS: Chlorhexidine digluconate dressings would reduce costs, local infections and CRBSIs, and deaths. Use of chlorhexidine digluconate dressings should be considered to prevent infections among patients with catheters.