AIMS: To examine trajectories of resilience over 25 years among individuals who as adolescents received treatment for substance misuse, the clinical sample (CS) and a matched general population sample (GP). DESIGN: Comparison of the CS and GP over 25 years using Swedish national registers of health care and criminality. SETTING: A substance misuse clinic for adolescents in an urban area in Sweden. MEASUREMENTS: Resilience was defined as the absence of substance misuse, hospitalizations for physical illnesses related to substance misuse, hospitalization for mental illness and law-abiding behaviour from ages 21 to 45 years. PARTICIPANTS: The CS included 701 individuals who as adolescents had consulted a clinic for substance misuse. The GP included 731 individuals selected randomly from the Swedish population and matched for age, sex and birthplace. FINDINGS: A total of 52.4% of the GP and 24.4% of the CS achieved resilience in all domains through 25 years. Among the CS, another one-third initially displayed moderate levels of resilience that rose to high levels over time, one-quarter displayed decreasing levels of resilience over time, while 9.3% showed little but improving resilience and 8.8% showed no resilience. Levels of resilience were associated with the severity of substance misuse and delinquency in adolescence. CONCLUSIONS: Individuals who had presented substance misuse problems in adolescence were less likely to achieve resilience over the subsequent 25 years than was a matched general population sample, and among them, four distinct trajectories of resilience were identified. The severity and type of problems presented in adolescence distinguished the four trajectories.