American Indians have among the highest prevalence rates for both substance use and obesity, yet there is a dearth of studies that have examined this relationship. We examined a subsample of American Indian adolescents (n=623), using the National Longitudinal Study of Adolescent to Adult Health. We examined the association between body mass index (BMI) and marijuana, other illicit drugs and heavy alcohol use, controlling for established predictors of youth substance use. We found that youth with lower BMIs used marijuana and other illicit drugs most frequently. Our findings support the notion that the relationship between weight status and substance use is a nuanced and complex one.