Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as an important cause of skin and soft-tissue infections (SSTI). The understanding of the molecular epidemiology and virulence of MRSA continues to expand. From January 2005 to December 2005, we screened soldiers for MRSA nasal colonization, administered a demographic questionnaire, and monitored them prospectively for SSTI. All MRSA isolates underwent molecular analysis, which included pulsed-filed gel electrophoresis (PFGE) and PCR for Panton-Valentine leukocidin (PVL), the arginine catabolic mobile element (ACME), and the staphylococcal cassette chromosome mec (SCCmec). Of the 3,447 soldiers screened, 134 (3.9%) had MRSA colonization. Of the 3,066 (89%) who completed the study, 39 developed culture-confirmed MRSA abscesses. Clone USA300 represented 53% of colonizing isolates but was responsible for 97% of the abscesses (P < 0.001). Unlike colonizing isolates, isolates positive for USA300, PVL, ACME, and type IV SCCmec were significantly associated with MRSA abscess isolates. As determined by multivariate analysis, risk factors for MRSA colonization were a history of SSTI and a history of hospitalization. Although various MRSA strains may colonize soldiers, USA300 is the most virulent when evaluated prospectively, and PVL, ACME, and type IV SCCmec are associated with these abscesses.