Historically, methods of interrupting pathogen transmission have focused on improving health care workers' adherence to recommended infection control practices. An adjunctive approach may be to use source control (eg, to decontaminate patients' skin). We performed a prospective sequential-group single-arm clinical trial in a teaching hospital's medical intensive care unit from October 2002 to December 2003. We bathed or cleansed 1787 patients and assessed them for acquisition of vancomycin-resistant enterococci (VRE). We performed a nested study of 86 patients with VRE colonization and obtained culture specimens from 758 environmental surfaces and 529 health care workers' hands. All patients were cleansed daily with the procedure specific to the study period as follows: period 1, soap and water baths; period 2, cleansing with cloths saturated with 2% chlorhexidine gluconate; and period 3, cloth cleansing without chlorhexidine. We measured colonization of patient skin by VRE, health care worker hand or environmental surface contamination by VRE, and patient acquisition of VRE rectal colonization. Compared with soap and water baths, cleansing patients with chlorhexidine-saturated cloths resulted in 2.5 log(10) less colonies of VRE on patients' skin and less VRE contamination of health care workers' hands (risk ratio [RR], 0.6; 95% confidence interval [CI], 0.4-0.8) and environmental surfaces (RR, 0.3; 95% CI, 0.2-0.5). The incidence of VRE acquisition decreased from 26 colonizations per 1000 patient-days to 9 per 1000 patient-days (RR, 0.4; 95% CI, 0.1-0.9). For all measures, effectiveness of cleansing with nonmedicated cloths was similar to that of soap and water baths. Cleansing patients with chlorhexidine-saturated cloths is a simple, effective strategy to reduce VRE contamination of patients' skin, the environment, and health care workers' hands and to decrease patient acquisition of VRE.