Prescription opioid misuse is a serious public health concern, yet antecedent factors are poorly described. Using data from the National Longitudinal Study of Adolescent to Adult Health (N = 14,784), we examined the longitudinal relationship between a history of adolescent chronic pain and the odds of misusing prescription opioids in adulthood. The primary predictor variable was chronic pain status during adolescence. The primary outcome variables were prescription opioid misuse during early adulthood and adulthood. Multivariate models controlled for known risk factors of opioid misuse, including sociodemographics (sex, race, and ethnicity), adolescent mental health symptoms (anxiety, depression), adolescent self-reported physical health status, adolescent substance use/abuse, childhood trauma, and adult legitimate opioid use. We found that adults with a history of adolescent chronic pain were more likely to misuse opioids than those without history of chronic pain, even after controlling for other known risk factors. Further, we found that among individuals with history of adolescent chronic pain that race (white), other substance use, and exposure to trauma were risk factors for later opioid misuse. Longitudinal associations between adolescent chronic pain and subsequent adult prescription opioid misuse highlight the need for early targeted screening and prevention efforts that may reduce later opioid misuse.Perspective: Using a large, nationally representative sample, we found that chronic pain during adolescence was an independent risk factor for opioid misuse in adulthood, over and above other known risk factors. Furthermore, among those individuals with adolescent chronic pain, substance use, exposure to trauma, and race were associated with opioid misuse.