Although more than 1 in every 3 US individuals will develop a substance use disorder (SUD) in their lifetime, relatively little is known about the long-term sequelae of SUD symptoms from adolescence through adulthood. To evaluate the longitudinal associations between adolescents' SUD symptom severity with later medical use of prescription drugs (ie, opioids, sedatives, and tranquilizers), prescription drug misuse (PDM), and SUD symptoms at ages 35 to 50 years. Eleven cohorts of US 12th grade students were followed longitudinally from age 18 years (1976-1986) to age 50 years (2008-2018) in the Monitoring the Future (MTF) study. Baseline surveys were self-administered in classrooms, and follow-ups were conducted by mail. Data were analyzed from June 2021 to February 2022. Response to MTF study between 1976 and 2018. Sociodemographic variables were measured at baseline. All bivariate and multivariate analyses use attrition weights to adjust for attrition by age 50 years within the sample. SUD symptoms, prescription drug use, and PDM were measured at baseline and every follow-up. The sample of 5317 individuals was 51.2% female (2685 participants; 95% CI, 49.6%-52.6%) and 77.9% White (4222 participants; 95% CI, 77.6%-79.1%). Participants were surveyed beginning at age 18 years and ending at age 50 years. The baseline response rate ranged from 77% to 84%, and the 32-year retention rate was 53%. Most adolescents with most severe SUD symptoms at age 18 years had 2 or more SUD symptoms in adulthood (316 participants [61.6%]; 95% CI, 55.7%-66.9%), and this association held for baseline alcohol, cannabis, and other drug use disorder symptoms. Adolescents with the highest SUD symptom severity at age 18 years had the highest adjusted odds of prescription drug use and PDM in adulthood (4-5 symptoms, adjusted odds ratio, 1.56; 95% CI, 1.06-2.32; ≥6 symptoms, adjusted odds ratio, 1.55; 95% CI, 1.11-2.16). The majority of adults using prescribed opioids, sedatives, or tranquilizers (568 participants [52.2%]; 95% CI, 48.4%-55.9%) in the past year had multiple SUD symptoms at age 18 years. These findings suggest that most adolescents with severe SUD symptoms do not transition out of symptomatic substance use, and the long-term sequelae for adolescents with more severe SUD symptoms are more deleterious than those for adolescents with no or low severity. Prescribers should be aware that many adults prescribed opioids, sedatives, or tranquilizers had multiple SUD symptoms during adolescence and require careful assessment and monitoring.