We assessed the effectiveness of a culturally grounded, multimedia, sexual risk reduction intervention called Circle of Life (mCOL), designed to increase knowledge and self-efficacy among preteen American Indians and Alaska Natives. Partnering with Native Boys and Girls Clubs in 15 communities across six Northern Plains reservations, we conducted a cluster randomized controlled trial among 10- to 12-year-olds (n = 167; mean age = 11.2). Club units were randomly assigned to mCOL (n = 8) or the attention-control program, After-School Science Plus (AS+; n = 7). Compared with the AS+ group, mCOL youth scored significantly higher on HIV/sexually transmitted infection (STI) knowledge questions at both follow-ups; self-efficacy to avoid peer pressure and self-efficacy to avoid sex were significantly higher at posttest; self-perceived volition was significantly higher at 9-month follow-up; and no differences were found for behavioral precursors to sex. mCOL had modest effects on precursors to sexual behavior, which may lead to less risky sexual behavior in later years.