BACKGROUND: Adolescents living with HIV have elevated mental distress and suboptimal antiretroviral therapy (ART) adherence. SETTING: Two urban clinics in Kigali, Rwanda. METHODS: A 2-arm individual randomized controlled trial compared Trauma-Informed Cognitive Behavioral Therapy enhanced to address HIV (TI-CBTe) with usual care (time-matched, long-standing, unstructured support groups) with 356 12- to 21-year-old (M = 16.78) Rwandans living with HIV. TI-CBTe included 6 group-based 2-hour sessions led by trained and supervised 21- to 25-year-old Rwandans living with HIV. Participants reported their ART adherence, depression/anxiety, and Post-Traumatic Stress Disorder symptoms at baseline, 6, 12, and 18 months. RESULTS: ART adherence was relatively high at baseline, and youth reported elevated rates of depression/anxiety and trauma symptoms. There were no differential treatment effects on adherence, but depression/anxiety improved over time. Youth with lower depression/anxiety at baseline seemed to benefit more from TI-CBTe than usual care, whereas women with high baseline distress seemed to benefit more from usual care. Youth were less likely to score in high Post-Traumatic Stress Disorder symptom categories at the follow-up, with no differential treatment effects. CONCLUSIONS: TI-CBTe did not outperform usual care on ART adherence, possibly reflecting relatively high adherence at baseline, simplified medication regimens over time, a strong comparison condition, or because youth assigned to TI-CBTe returned to their support groups after the intervention. TI-CBTe was more effective for youth with lower depression/anxiety symptoms, whereas youth with high distress benefitted more from the support groups. TI-CBTe was feasible and acceptable, and young adults living with HIV were able to deliver a mental health intervention with fidelity. The powerful nature of the comparison group, ongoing support groups, points to the potential value of locally crafted interventions in low-resource settings.