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Background: There is growing optimism regarding the use of screening and brief intervention (SBI) to identify and reduce risk behaviors during adolescence. However, understanding successful SBI implementation remains unclear. We previously reported the effects of CONNECT, a school-based SBI, on reducing the primary outcome, the rate of monthly alcohol use among primarily American Indian (AI) and White high school students in the Cherokee Nation. In this paper, we describe the design and implementation process for CONNECT. Method: CONNECT was designed to reduce alcohol use with 2 key strategies: (1) SBI with motivational interviewing (MI), implemented by a school-based CONNECT coach, and (2) a media campaign. Results: Implementation results indicate that during each semester of the 2-1/2 years, between 73% and 100% of eligible students had at least one 15-minute meeting with a CONNECT coach. Postcards and posters with positive communication tips for parents were displayed in CONNECT communities. No statistically significant differences occurred between the CONNECT and control groups on the hypothesized intermediate outcomes. Conclusions: We describe implementation of a universal, school-based, culturally adapted SBI that was effective in reducing alcohol use among youth living in the Cherokee Nation. Schools provide an important context for universal delivery of SBI interventions, such as CONNECT, for diverse adolescent populations, including AI youth.