In order to develop a comprehensive substance abuse prevention plan for a boarding school for American Indian middle school students, the students (N = 66) were surveyed at two time points and teacher reports and discipline records were collected. Factors most strongly related to substance use were affiliation with risk-taking peers, lower levels of assertiveness and self-esteem, and being female. Girls also had higher levels of distress, social anxiety, and association with risk-taking peers. Several recommendations for a prevention program are made, including the elimination of a separate "Honor Dorm" for well-behaved students, the creation of mentored friendship groups, and the training of peer leaders.