IMPORTANCE The rise of methicillin-resistant Staphylococcus aureus (MRSA) infections in the outpatient setting has led to a growing trend of empirical antibiotic treatment for MRSA. The limited oral antibiotics available and the growing resistance to these antibiotics make this a controversial practice. OBJECTIVE To determine the frequency of patients with MRSA skin and soft-tissue infections (SSTIs) reverting tomethicillin-susceptible Staphylococcus aureus (MSSA) positivity. DESIGN AND SETTING Retrospective medical record review of inpatients and outpatients from our university hospital and clinics between January 1, 2000, and December 31, 2010. PARTICIPANTS Patients in our institutional microbiological database were included if they had a MRSA-positive SSTI and subsequent culture-proven S aureus SSTI more than 1 month later. No sociodemographic restrictions were applied. A sample of at least 200 patients meeting the above criteria was desired. The database was sorted by ascending medical record number, with the first 1681 patients' medical records reviewed. Of these, 215 patients met our criteria. MAIN OUTCOMES AND MEASURES Whether a patient remained MRSA positive in subsequent SSTIs or reverted to MSSA-positive infections. RESULTS Of the total 215 patients, 64 (29.8%) had at least 1 incident of MSSA reversion, and 55 (25.6%) reverted to MSSA infections for the remainder of the study.We assessed various factors that might increase or decrease the likelihood of reversion. The presence of an invasive device was the only factor to demonstrate a statistically significant risk (relative risk, 1.20; 95%CI, 1.02-1.41; P = .03) toward remaining MRSA positive in subsequent infections. CONCLUSIONS AND RELEVANCE Patients with MRSA SSTIs demonstrated the ability to revert to subsequent MSSA SSTIs with a significant frequency. Further study regarding MRSA risk factors and their effects on subsequent infections would be valuable in guiding empirical treatment. Reculturing new infections in previously MRSA-positive patients is a prudent management strategy as we recognize that susceptibilities of the S aureus organisms change.