Purpose: Prevalence estimates for drug use health risk behaviors among high school students are widely available, but relatively few studies describe how and to what extent these risk behaviors occur together. Furthermore, little research has examined whether the co-occurrence of health risk behaviors varies by key demographic characteristics such as gender and race/ethnicity. The purpose of this study is to develop prevalence estimates for combinations of co-occurring drug use health risk behaviors among United States high school students, and to investigate demographic differences in co-occurrence. Methods: Survey data from a representative sample of United States high school students (N = 16,410) were analyzed. This research is on four health risk behaviors: tobacco use, alcohol use, marijuana use, and cocaine use. Explicit descriptions of the risk behavior combinations that students engage in are presented, and comparisons are made among gender, grade, and racial/ethnic student groups using chi-squared tests. Results and Conclusions: Study results suggest that most adolescents do not engage in multiple risk behaviors simultaneously and that race, gender, and grade level significantly impact the prevalence of co-occurring risk behaviors.