We systematically searched 9 biomedical and social science databases (1980-2012) for primary and secondary interventions that prevented or reduced 2 or more adolescent health risk behaviors (tobacco use, alcohol use, illicit drug use, risky sexual behavior, aggressive acts). We identified 44 randomized controlled trials of universal or selective interventions and were effective for multiple health risk behaviors. Most were school based, conducted in the United States, and effective for multiple forms of substance use. Effects were small, in line with findings for other universal prevention programs. In some studies, effects for more than 1 health risk behavior only emerged at long-term follow-up. Integrated prevention programs are feasible and effective and may be more efficient than discrete prevention strategies.