Reservation-area American Indian (AI) youth demonstrate higher rates of binge drinking (BD) than their non-AI peers. However, individual and school-level differences in BD disparities between reservation-area AI/non-AI female and male adolescents remain unexamined. This study applies an Intersectional framework to examine risk and protective factors of BD among reservation-area youth at the intersection of their sex and AI identities. A nationally representative sample of adolescents (N = 14,769; Mage = 14.6, 49% female; 61% AI) attending 103 reservation-serving schools completed a survey between 2015 and 2019. Multilevel modeling was used to examine differences in risk and protective factors of BD between AI and non-AI male and female adolescents. Our findings indicate that the effects of student and school-level risk and protective factors on adolescents' BD are driven primarily by sex within AI and non-AI groups. Implications for future confirmatory research and tailoring school-based prevention programs are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).