IMPORTANCE: Suicide is a leading cause of death among 10- to 24-year-old individuals in the United States; evidence on effective treatment for adolescents who engage in suicidal and self-harm behaviors is limited. OBJECTIVE: To evaluate the efficacy of dialectical behavior therapy (DBT) compared with individual and group supportive therapy (IGST) for reducing suicide attempts, nonsuicidal self-injury, and overall self-harm among high-risk youths. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted from January 1, 2012, through August 31, 2014, at 4 academic medical centers. A total of 173 participants (pool of 195; 22 withdrew or were excluded) 12 to 18 years of age with a prior lifetime suicide attempt (≥3 prior self-harm episodes, suicidal ideation, or emotional dysregulation) were studied. Adaptive randomization balanced participants across conditions within sites based on age, number of prior suicide attempts, and psychotropic medication use. Participants were followed up for 1 year. INTERVENTIONS: Study participants were randomly assigned to DBT or IGST. Treatment duration was 6 months. Both groups had weekly individual and group psychotherapy, therapist consultation meetings, and parent contact as needed. MAIN OUTCOMES AND MEASURES: A priori planned outcomes were suicide attempts, nonsuicidal self-injury, and total self-harm assessed using the Suicide Attempt Self-Injury Interview. RESULTS: A total of 173 adolescents (163 [94.8%] female and 97 [56.4%] white; mean [SD] age, 14.89 [1.47] years) were studied. Significant advantages were found for DBT on all primary outcomes after treatment: suicide attempts (65 [90.3%] of 72 receiving DBT vs 51 [78.9%] of 65 receiving IGST with no suicide attempts; odds ratio [OR], 0.30; 95% CI, 0.10-0.91), nonsuicidal self-injury (41 [56.9%] of 72 receiving DBT vs 26 [40.0%] of 65 receiving IGST with no self-injury; OR, 0.32; 95% CI, 0.13-0.70), and self-harm (39 [54.2%] of 72 receiving DBT vs 24 [36.9%] of 65 receiving IGST with no self-harm; OR, 0.33; 95% CI, 0.14-0.78). Rates of self-harm decreased through 1-year follow-up. The advantage of DBT decreased, with no statistically significant between-group differences from 6 to 12 months (OR, 0.65; 95% CI, 0.12-3.36; P = .61). Treatment completion rates were higher for DBT (75.6%) than for IGST (55.2%), but pattern-mixture models indicated that this difference did not informatively affect outcomes. CONCLUSIONS AND RELEVANCE: The results of this trial support the efficacy of DBT for reducing self-harm and suicide attempts in highly suicidal self-harming adolescents. On the basis of the criteria of 2 independent trials supporting efficacy, results support DBT as the first well-established, empirically supported treatment for decreasing repeated suicide attempts and self-harm in youths. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01528020.