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Health care-associated infections (HAIs) result in increased patient morbidity and utilization of health care resources. Rates of HAI are increasing despite advances in health care technology. Limited antimicrobial agents and a dry drug pipeline make novel prevention efforts critical. Chlorhexidine, an antiseptic solution that has been used worldwide since the 1950s, is a safe and effective product with broad antiseptic activity. Novel uses of chlorhexidine-containing products are being implemented to promote antisepsis and prevent bacterial colonization and infection. We review some of the many infection control applications of chlorhexidine in the battle against HAI, such as general skin cleansing, skin decolonization, preoperative showering and bathing, vascular catheter site preparation, impregnated catheter site dressings, impregnated catheters, and oral decontamination. As mandatory public reporting and pay for performance force infection control issues to the forefront, chlorhexidine-containing products may provide a vast armamentarium for the control and prevention of HAI.