ABSTRACT Globally, there are over 16 million orphans and vulnerable children (OVC), with estimates of between 1.9-3.7 million for South Africa (SA). Despite high mental health needs of OVC, there is a crisis in scarcity of mental health workers in SA. Community-based organizations (CBOs) offer a strategic point of intervention. In a prior NIH-funded quasi-experimental feasibility trial we showed that the Mediational Intervention for Sensitizing Caregivers (MISC) for CBO careworkers, thereafter named MISC-CBO, significantly reduced mental health problems in Sesotho-speaking OVC. MISC-CBO is a year-long semi-structured, manualized video-feedback intervention designed to enhance the caregiving capacity of CBO careworkers to improve child outcomes, by targeting the RDoC systems for social processes (affiliation and attachment). Building on this work, we now propose a repeated measures cluster randomized trial to fully establish the effectiveness and trans-diagnostic mechanisms of action of MISC-CBO in 7-11 year olds – a developmental stage critical for building mental health resilience against the adolescent onset of psychiatric problems. In addition, we will use Consolidated Framework for Implementation Research (CFIR) constructs and input from a Community Advisory Board (CAB) to leverage the RCT to evaluate implementation costs, climate and readiness that would better position the RCT results for future uptake, scale up, and sustainability. In Aim 1, we will evaluate the direct effects of MISC-CBO on video- coded CBO careworker caregiving quality (affiliation and attachment) and children’s mental health outcomes over a 24 month period. 24 CBOs (360 children and 72 careworkers) will be recruited using our existing NGO partner (Childline) in the Mangaung and Xhariep districts in the Free State, SA. CBOs will be randomly assigned to receive either one year of bi-weekly MISC-CBO or TAU. We hypothesize that MISC-CBO will be associated with comparative increases in careworker caregiving quality and reductions in mental health problems in OVC. In Aim 2a, we will test the hypothesis that caregiving quality at end-of-intervention (12 months) accounts for intervention effects on child mental health at 18 and 24 months. Aim 2b will evaluate the moderating effects of orphan status and the quality of the home environment, expecting that OVC who are maternal and double orphans, and from impoverished home environments will show reduced response to intervention compared to children without these risk factors. Aim 3a will use World Health Organization metrics to test the hypothesis that MISC-CBO is cost-effective in terms of disability-adjusted life years (DALYs) averted. Aim 3b will use qualitative methodology to test the hypothesis that community stakeholders deem the climate favorable and ready for the implementation of MISC-CBO, and that additional barriers and facilitators for scale-up and implementation will be identified. Our proposed work extends our format...