OBJECTIVE To identify when youth are most likely to start using prescription pain relievers to get high or for other unapproved indications outside the boundaries of what a prescribing physician might intend (ie, extramedical use). DESIGN Cross-sectional surveys of adolescent cohorts, 2004 to 2008. SETTING The United States. PARTICIPANTS Large nationally representative samples of youth in the United States who had been assessed for the 2004 through 2008 National Survey on Drug Use and Health, yielding data from 138729 participants aged 12 to 21 years. MAIN OUTCOME MEASURES Estimated age-specific risk of starting extramedical use of prescription pain relievers, year by year, and confirmation of age at peak risk by tracing the experience of individual cohorts during this period. RESULTS The estimated peak risk of starting extramedical use of prescription pain relievers occurs in midadolescence, well before the college years. The age at peak risk is 16 years, when an estimated 2% to 3% become newly incident users. Smaller risk estimates are observed at age 12 to 14 years and at age 19 to 21 years. CONCLUSIONS For initiatives to prevent youth from using prescription pain relievers to get high or for other unapproved indications, a focus on the last year of high school and the post-secondary school years may be too little too late. Practice-based approaches are needed in addition to public health interventions based on effective alcohol and tobacco prevention programs during the earlier adolescent years.