The objective of this study was to examine the prevalence and patterns associated with past-year medical use, medical misuse, and nonmedical use of prescription opioids (NMUPO) among adolescents over a 2-year time period and to examine substance abuse, sleeping problems, and physical pain symptoms associated with these patterns of medical use, medical misuse, and NMUPO. A Web-based survey was self-administered by a longitudinal sample of 2050 middle and high school students in 2009-2010 (Year 1) and again in 2010-2011 (Year 2). The study was set in 2 southeastern Michigan school districts. The longitudinal sample consisted of 50% females, 67% Whites, 28% African-Americans, and 5% from other racial/ethnic categories. Main outcome measures were past-year medical use, medical misuse, and NMUPO. Of those reporting appropriate medical use of prescription opioids in Year 1, approximately 34% continued medical use in Year 2. Of those reporting past-year NMUPO in Year 1, approximately 25% continued NMUPO in Year 2. Appropriate medical use and NMUPO for pain relief was more prevalent among girls than boys. Multiple logistic regression analyses indicated that the odds of a positive screen for substance abuse in Year 2 were greater for adolescents who reported medical misuse or NMUPO for non-pain-relief motives in Year 1 compared with those who did not use prescription opioids. The findings indicate an increased risk for substance abuse among adolescents who report medical misuse or NMUPO for non-pain-relief motives over time. The findings have important clinical implications for interventions to reduce medical misuse and NMUPO among adolescents.