Background <p>Depression is a leading cause of disability among adolescents, with the burden disproportionately affecting low- and middle-income countries (LMICs) where access to mental health care is limited. Interpersonal therapy (IPT), a structured psychological intervention, has shown promise in treating adolescent depression but there is limited evidence from LMICs and research on how it works and in which contexts it works best. This protocol describes a realist cluster-randomised controlled trial (cRCT) assessing the effectiveness, cost-utility and mechanisms of school-based group IPT for adolescents with depression in Nepal.</p> Methods <p>This superiority phase III cRCT will be conducted in 48 public secondary schools across Chitwan and Nawalpur districts, with schools randomised 1:1 to intervention or enhanced usual care. Adolescents aged 13–19 with depression (Patient Health Questionnaire modified for adolescents, PHQ-A score ≥11) will be recruited from grades 7–9. The intervention comprises two individual and ten weekly group IPT sessions delivered by trained lay facilitators. Adolescents will be surveyed pre-randomisation (baseline) and five (midline), 17 (endline) and 32 weeks (follow-up) post randomisation. The primary outcome is depression severity at 17 weeks post-randomisation assessed using the PHQ-A. Secondary outcomes include anxiety, post-traumatic stress disorder, functional impairment, school attendance and quality of life. Intermediate outcomes including hope, emotion regulation, and social support will be assessed to examine mechanisms of change. A priori hypotheses concerning IPT’s mechanisms and contextual factors influencing these (context-mechanism-outcome configurations) will be refined through analysis of qualitative process data and tested in mediation, moderation and moderated mediation analyses of trial data. Economic evaluation will estimate cost-utility and benefit-cost ratios from both provider and modified societal perspectives. The process evaluation will assess fidelity, reach, and acceptability in various school settings.</p> Discussion <p>This trial is the first to integrate realist evaluation into a cRCT of a psychological intervention for adolescents in a LMIC and has potential to advance research and practice by elucidating how IPT works in a real-world context. If IPT is effective in Nepal, it could be scaled up through the education system as a part of a comprehensive school mental health care package.</p> Trial registration <p>ISRCTN52852397 (registered 21/03/2025).</p>