Background: Community-associated Staphylococcus aureus infections often affect multiple members of a household. We compared 2 approaches to S. aureus eradication: decolonizing the entire household versus decolonizing the index case alone. Methods: An open-label, randomized trial enrolled 183 pediatric patients (cases) with community-onset S. aureus skin abscesses and colonization of anterior nares, axillae, or inguinal folds from 2008 to 2009 at primary and tertiary centers. Participants were randomized to decolonization of the case alone (index group) or of all household members (household group). The 5-day regimen included hygiene education, twice-daily intranasal mupirocin, and daily chlorhexidine body washes. Colonization of cases and subsequent skin and soft tissue infection (SSTI) in cases and household contacts were ascertained at 1, 3, 6, and 12 months. Results: Among 147 cases with 1-month colonization data, modified intention-to-treat analysis revealed S. aureus eradication in 50% of cases in the index group and 51% in the household group (P 5 1.00). Among 126 cases completing 12-month follow-up, S. aureus was eradicated from 54% of the index group versus 66% of the household group (P 5 .28). Over 12 months, recurrent SSTI was reported in 72% of cases in the index group and 52% in the household group (P 5 .02). SSTI incidence in household contacts was significantly lower in the household versus index group during the first 6 months; this trend continued at 12 months. Conclusions. Household decolonization was not more effective than individual decolonization in eradicating community-associated S. aureus carriage from cases. However, household decolonization reduced the incidence of subsequent SSTI in cases and their household contacts.