BACKGROUND. Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) causes skin and soft-tissue infection (SSTI) in military recruits. OBJECTIVE. To evaluate the effectiveness of 2% chlorhexidine gluconate (CHG)-impregnated cloths in reducing rates of SSTI and S. aureus colonization among military recruits. DESIGN. A cluster-randomized (by platoon), double-blind, controlled effectiveness trial. SETTING. Marine Officer Candidate School, Quantico, Virginia, 2007. PARTICIPANTS. Military recruits. INTERVENTION. Application of CHG-impregnated or control (Comfort Bath; Sage) cloths applied over entire body thrice weekly. MEASUREMENTS. Recruits were monitored daily for SSTI. Baseline and serial nasal and/or axillary swabs were collected to assess S. aureus colonization. RESULTS. Of 1,562 subjects enrolled, 781 (from 23 platoons) underwent CHG-impregnated cloth application and 781 (from 21 platoons) underwent control cloth application. The rate of compliance (defined as application of 50% or more of wipes) at 2 weeks was similar (CHG group, 63%; control group, 67%) and decreased over the 6-week period. The mean 6-week SSTI rate in the CHG-impregnated cloth group was 0.094, compared with 0.071 in the control group (analysis of variance model rate difference, 0.025 ± 0.016; P=.14). At baseline, 43% of subjects were colonized with methicillin- susceptible S. aureus (MSSA), and 2.1% were colonized with MRSA. The mean incidence of colonization with MSSA was 50% and 61% (P=.026) and with MRSA was 2.6% and 6.0% (P=.034) for the CHG-impregnated and control cloth groups, respectively. CONCLUSIONS. CHG-impregnated cloths applied thrice weekly did not reduce rates of SSTI among recruits. S. aureus colonization rates increased in both groups but to a lesser extent in those assigned to the CHG-impregnated cloth intervention. Antecedent S. aureus colonization was not a risk factor for SSTI. Additional studies are needed to identify effective measures for preventing SSTI among military recruits. CLINICAL TRIALS REGISTRATION. ClinicalTrials.gov identifier: NCT00475930.