This study examined neighborhood effects on the drug use of American Indian youth of the Southwest. We compared these effects with American Indian and non-American Indian youth in order to examine the universality of neighborhood disorganization as a risk factor for drug use. Neighborhood level variables included unemployment, poverty, education, and violent crime rate. Results indicated that American Indian youth were not as adversely affected by these neighborhood factors. American Indian youth may possess cultural characteristics that protect them from the adverse effects of neighborhood disorganization, including close familial relationships and ethnic pride. Culturally competent practice with American Indian youth may best be implemented through the enhancement of relational and cultural strengths as described in the literature.