A cluster-randomized trial evaluating the effectiveness of chlorhexidine gluconate-impregnated wipes against skin and soft tissue infections (SSTIs) and colonization with methicillin-resistant Staphylococcus aureus (MRSA) was conducted among military recruits attending Officer Candidate School at Marine Corps Base Quantico, Virginia. Participants were instructed to use the wipes thrice weekly and were monitored daily for SSTI. Surveys assessed frequency of wipe use as well as knowledge and attitudes regarding MRSA SSTI. Use of chlorhexidine gluconate-impregnated wipes failed to prevent SSTI; however, study adherence was moderate. Adherence with the study regimen (defined as use of > or = 50% of the wipes) was 65% at week 2 and declined to 49% by week 6. Adherence was approximately 59% in the first two classes and declined in later classes. One-third felt that use of the wipes was disruptive. Participants were knowledgeable about MRSA SSTI prevention measures. However, only 53% agreed that MRSA commonly causes skin infections in military training facilities. Understanding adherence and its determinants is needed to optimize prevention strategies that require self-administration. Future efforts should address barriers to adherence with prevention strategies in recruit training settings.