Objective: To determine whether the predominant pattern of the sequence of use of different classes of substances among a large sample of American Indian (Al) adolescents is consistent with Stage Theory [i.e., (1) alcohol, (2) marijuana, (3) other illicit drugs, and (4) cocaine]. Method: Data came from surveys completed by 1,562 Al high school students in 1993. Pairwise comparisons of age of first use for alcohol, marijuana, inhalants, cocaine, and other illicit drugs were examined, as were the prevalence rates of specific sequences of substance use. Results: Thirty-five percent of the Al youths who had used both alcohol and marijuana reported using alcohol first. Seventy-five percent of youths who had used three or more substances reported a sequence of first use that was inconsistent with Stage Theory. However, a general pattern of using alcohol, marijuana, and/or inhalants prior to the use of cocaine and other illicit drugs was observed. Sequences of first use varied by gender, age of first substance use, community, and number of classes of substances used. Conclusions: To enhance the validity of Stage Theory for Al adolescents, the authors recommend its revision to include alcohol, marijuana, and inhalants as initiating substances.