Culturally relevant interventions have the potential to improve adolescent health and protective factors associated with sexual risk taking. We evaluated the impact of the Native STAND curriculum with American Indian and Alaska Native (AI/AN or Native) high school students living across the U.S. using a pre-post evaluation design. Native STAND is a comprehensive sexual health curriculum for Native high school students that focuses on sexually transmitted infections, HIV/AIDS, and teen pregnancy prevention, while also covering drug and alcohol use, suicide, and dating violence. The curriculum was implemented in 48 AI/AN communities from 2014 to 2019. A significantly higher percentage of youth reported at post-test having a serious conversation about sex with their friends (post 36% vs. pre 28%, p
< 0.001), thinking about lessons learned (post 24% vs. pre 7%, p
< 0.0001), and sharing lessons learned during the conversation (post 21% vs. pre 4%, p
< 0.001). A lower percentage of AI/AN youth reported being bullied in the last year (post 31% vs. pre 37%, p
< 0.001). Family social support was moderated by dose, with subscale scores of 3.75 at post-with <27 sessions vs. 3.96 at post-with all 27 sessions (p
= 0.02). The results demonstrate the effectiveness of Native STAND when delivered in a variety of settings. Efforts are now underway to update Native STAND for medical accuracy, improve alignment with typical class periods, and promote its use and an effective EBI for AI/AN youth.