INTRODUCTION: Low- and middle-income countries shoulder a disproportionate burden of mental health disorders with limited resources to support the provision of care using culturally relevant, evidence-based interventions. This is particularly true in Cambodia where the population continues to confront traumatic consequences of the Khmer Rouge genocide that targeted educated people, including treatment providers. Trauma-Informed Treatment Algorithms for Advancing Novel Outcomes (Project TITAN) will examine proof of concept and preliminary efficacy of culturally tailored interventions for symptoms of post-traumatic stress (PTS) among Cambodian adults. METHODS: A stepped care randomized controlled trial enrolling people seeking mental health treatment and priority populations with high rates of trauma exposure, including female entertainment and sex workers and sexual and gender minorities. In total, 160 participants with symptoms of PTS are randomized to Stabilization Techniques or Behavioral Activation plus Stabilization Techniques, implemented within a culturally relevant framework. Individuals who do not demonstrate a reduction in symptoms of PTS after six treatment sessions receive Eye Movement Desensitization and Reprocessing therapy. PTS, depression, anxiety, and substance use are assessed at baseline and two and four months post-randomization. PLANNED ANALYSES: The percentage of individuals achieving reductions in symptoms of PTS after four months is the primary outcome. Secondary outcomes are depression, anxiety, and substance use over four months. Finally, machine learning analyses will be conducted to identify features at baseline and during treatment that predict outcomes. DISCUSSION: Findings will guide future development and implementation of interventions to improve mental health conditions among individuals in Cambodia and other resource-limited settings.