The objective of this study was to examine the association of context of prescription opioid exposure (ie, medical or nonmedical) in adolescence with the subsequent risk of nonmedical use of prescription opioids (NMUPO) and substance use disorder (SUD) symptoms at age 35. Multiple cohorts of nationally representative probability samples of U.S. high school seniors (n = 4072) were surveyed through self-administered questionnaires and followed longitudinally from adolescence (modal age 18, graduating classes 1976-1996) to age 35 (1993-2013). Main outcome measures were past-year NMUPO and SUD symptoms. The medical and NMUPO during adolescence was significantly associated with NMUPO at age 35. Relative to no prescription opioid exposure, medical use of prescription opioids without any history of NMUPO during adolescence was not associated with SUD symptoms at age 35. In contrast, compared with no prescription opioid exposure during adolescence, the adjusted odds ratios (AORs) associated with SUD symptoms at age 35 were greater among those with a history of both medical use of prescription opioids and NMUPO during adolescence, AOR = 1.49 (95% CI = 1.13-1.97); and among those who reported NMUPO only, AOR = 2.61 (95% CI = 1.88-3.61). The findings indicate medical use of prescription opioids without any history of NMUPO in adolescence is not associated with SUD symptoms at age 35, whereas any NMUPO in adolescence predicts SUD symptoms at age 35. Screening instruments and preventive intervention programs to reduce NMUPO and SUDs must account for the context associated with prescription opioid exposure during adolescence.