BACKGROUND: Legal performance-enhancing substance(s) (PES) (eg, creatine) are widely used among adolescent boys and young men; however, little is known about their temporal associations with substance use behaviors. METHODS: We analyzed prospective cohort data from the National Longitudinal Study of Adolescent to Adult Health, Waves I to IV (1994-2008). Logistic regressions were used to first assess adolescent substance use (Wave I) and use of legal PES (Wave III) and second to assess use of legal PES (Wave III) and subsequent substance use-associated risk behaviors (Wave IV), adjusting for potential confounders. RESULTS: Among the sample of 12 133 young adults aged 18 to 26 years, 16.1% of young men and 1.2% of young women reported using legal PES in the past year. Adolescent alcohol use was prospectively associated with legal PES use in young men (odds ratio 1.39; 95% confidence interval [CI] 1.13-1.70). Among young men, legal PES use was prospectively associated with higher odds of problematic alcohol use and drinking-related risk behaviors, including binge drinking (adjusted odds ratio [aOR] 1.35; 95% CI 1.07-1.71), injurious and risky behaviors (aOR 1.78; 95% CI 1.43-2.21), legal problems (aOR 1.52; 95% CI 1.08-2.13), cutting down on activities and socialization (aOR 1.91; 95% CI 1.36-2.78), and emotional or physical health problems (aOR 1.44; 95% CI 1.04-1.99). Among young women, legal PES use was prospectively associated with higher odds of emotional or physical health problems (aOR 3.00; 95% CI 1.20-7.44). CONCLUSIONS: Use of legal PES should be considered a gateway to future problematic alcohol use and drinking-related risk behaviors, particularly among young men.