Long-term effectiveness of a peer-led asthma self-management program in improving asthma outcomes in adolescents living in urban areas has not been established.To determine the long-term effects of a peer-led program on asthma control, quality of life, and asthma management among predominantly racial and ethnic minority adolescents living in urban areas.A parallel-group, randomized clinical trial was conducted in 2015 to 2019 in 3 metropolitan cities in the US: Buffalo, New York; Baltimore, Maryland; and Memphis, Tennessee. Adolescents aged 12 to 17 years old with persistent asthma were recruited mainly through clinical practices and schools. Participants were followed-up for 15 months after the intervention. Double-blinding was achieved for baseline. Data analysis was performed from June 2019 to June 2020.The intervention group received a peer-led asthma self-management program; the control group received the identical program led by adult health care professionals. Peer leaders made follow-up contacts every other month for 12 months.The primary outcome was quality of life measured by the Pediatric Asthma Quality of Life Questionnaire, which consists of 3 subscales that measure symptoms (10 items), activity limitations (5 items), and emotional functioning (8 items) in the past 2 weeks. Each item was measured on a 7-point scale, with higher mean scores indicating better quality of life. Secondary measures included the Asthma Control Questionnaire and an asthma self-management index capturing steps to prevent and manage symptoms, self-efficacy, and lung function.Of 395 eligible adolescents, 35 refused, 38 did not show or were lost to contact, and 2 withdrew before randomization; 320 adolescents participated (mean [SD] age, 14.3 [1.71] years), including 168 boys (52.5%), 251 Black or African American adolescents (78.4%), and 232 adolescents (72.5%) with public health insurance. Of 320 enrolled, 303 were included in the longitudinal analysis. Response rates were 80% or higher at all time points. The peer-led group had greater improvement in outcomes than the adult-led group, with adjusted mean differences (AMDs) between baseline and 15 months of 0.75 vs 0.37 for quality of life (between-group AMD, 0.38; 95% CI, 0.07 to 0.63) and -0.59 vs -0.31 for asthma control (between-group AMD, -0.28; 95% CI, -0.51 to -0.01). Outcomes were not affected by bimonthly contact doses.In this randomized clinical trial, a peer-led asthma self-management education was more effective than an adult-led program in improving asthma outcomes, with the improvements sustained for up to 15 months. These findings suggest that a peer-led asthma self-management program should be considered in addressing the disproportionate asthma burden in racial and ethnic minority adolescents living in urban communities.ClinicalTrials.gov Identifier: NCT02293499.