AbstractPurpose There is a need to obtain greater clarity regarding adolescents' e-cigarette use and the associations of use with a wider range of risk behaviors. This study examines the associations among past-month e-cigarette use only, traditional cigarette smoking only, dual use (i.e., concurrent e-cigarette use and cigarette smoking), school-related (i.e., truancy and poor academic performance) risk behaviors, and substance-related (i.e., alcohol use, binge drinking, marijuana use, illicit drug use, and nonmedical prescription drug use) risk behaviors. Methods Data were collected via self-administered questionnaires from a nationally representative sample of 8,696 high school seniors. Results An estimated 9.9% of U.S. high school seniors reported past-month e-cigarette use only, 6.0% reported past-month cigarette smoking only, and 7.3% reported past-month dual use. School- and substance-related risk behaviors had strong associations with past-month e-cigarette use. Adolescents who only used e-cigarettes had significantly greater odds of all school- and substance-related risk behaviors relative to nonusers. Dual users had significantly greater odds of frequent/daily e-cigarette use as well as all school- and substance-related risk behaviors relative to those who only used e-cigarettes. Finally, adolescents who engaged in frequent/daily e-cigarette use had significantly greater odds of binge drinking, marijuana use, other illicit drug use and nonmedical prescription drug use, relative to experimental e-cigarette users. Conclusions E-cigarette use is common among U.S. adolescents, and there are robust associations between e-cigarette use and school- and substance-related risk behaviors. There is evidence that e-cigarette use clusters with risk behaviors and appears to represent a problem behavior, especially dual use of e-cigarettes and traditional cigarettes.