OBJECTIVE To identify risk factors for recurrent methicillin-resistant Staphylococcus aureus (MRSA) colonization. DESIGN Prospective cohort study conducted from January 1, 2010, through December 31, 2012. SETTING Five adult and pediatric academic medical centers. PARTICIPANTS Subjects (ie, index cases) who presented with acute community-onset MRSA skin and soft-tissue infection. METHODS Index cases and all household members performed self-sampling for MRSA colonization every 2 weeks for 6 months. Clearance of colonization was defined as 2 consecutive sampling periods with negative surveillance cultures. Recurrent colonization was defined as any positive MRSA surveillance culture after clearance. Index cases with recurrent MRSA colonization were compared with those without recurrence on the basis of antibiotic exposure, household demographic characteristics, and presence of MRSA colonization in household members. RESULTS The study cohort comprised 195 index cases; recurrent MRSA colonization occurred in 85 (43.6%). Median time to recurrence was 53 days (interquartile range, 36-84 days). Treatment with clindamycin was associated with lower risk of recurrence (odds ratio, 0.52; 95% CI, 0.29-0.93). Higher percentage of household members younger than 18 was associated with increased risk of recurrence (odds ratio, 1.01; 95% CI, 1.00-1.02). The association between MRSA colonization in household members and recurrent colonization in index cases did not reach statistical significance in primary analyses. CONCLUSION A large proportion of patients initially presenting with MRSA skin and soft-tissue infection will have recurrent colonization after clearance. The reduced rate of recurrent colonization associated with clindamycin may indicate a unique role for this antibiotic in the treatment of such infection.