An outbreak of methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTIs) occurred in a college football team in August 2006. Of 109 players on the team roster, 88 (81%) were interviewed during a cohort investigation. Twenty-five cases were identified, six of which were culture-confirmed. Available culture isolates were typed by pulsed-field gel electrophoresis (PFGE), which identified two different MRSA strains associated with the outbreak. Playing positions with the most physical contact (offensive linemen, defensive linemen, and tight ends) had the greatest risk of infection [risk ratio (RR) 5.1, 95% confidence interval (CI) 2.3-11.5. Other risk factors included recent skin trauma (RR 1.9, 95% CI 0.95-3.7), use of therapeutic hydrocollator packs (RR 2.5, 95% CI 1.1-5.7), and miscellaneous training equipment use (RR 2.1, 95% CI 1.1-4.1). The outbreak was successfully controlled through team education and implementation of improved infection-control practices and hygiene policies.