INTRODUCTION: Substance use (SU) and other mental health conditions, such as depression, contribute to poor engagement in HIV and TB care in South Africa, a country with the highest global prevalence of HIV and a significant TB burden. Yet, community health workers (CHWs)-frontline lay health workers who play a central role in re-engaging patients in HIV/TB care-receive little-to-no training on supporting patients with SU or other mental health concerns. CHWs also display stigma towards patients with SU and depression, which may contribute to HIV/TB care disengagement. We developed and tested a CHW training ("Siyakhana") to reduce CHW stigma towards SU and depression in HIV/TB care. METHODS: A cluster randomized, stepped-wedge hybrid type 2 effectiveness-implementation trial (N = 82 CHWs) evaluated Siyakhana across six clinics in a low-resource area of Cape Town, SA. The three-day Siyakhana training included psychoeducation, self-care strategies, non-judgmental communication, problem solving, and contact-based stigma reduction using lived experience narratives. Pre-training and three- and six-month post-training assessments were conducted. Primary effectiveness outcomes were CHW stigma towards SU and depression, assessed using the Social Distance Scale. Primary implementation outcomes were guided by Proctor's model, including fidelity, acceptability, appropriateness, and feasibility, assessed using structured coding of role plays and a validated quantitative measure for assessing implementation outcomes in low- and middle-income countries. RESULTS: Participants were on average 46.8 years old (SD = 8.9), 99% female, and 100% Black African. Ninety-five percent of CHWs completed the Siyakhana training, with approximately 90% retention over six months. A linear mixed effects model showed a significant effect of the Siyakhana training on reducing SU stigma over six months after adjusting for time (β = -1.46, SE = 0.67, p <
0.05), but no effect on depression stigma (β = -0.20, SE = 0.57, p >
0.05). CHW fidelity was 89.4% (SD = 11.3%) at six-months. Quantitative implementation outcomes indicated high acceptability (M = 2.85, SD = 0.27), appropriateness (M = 2.77, SD = 0.31), and feasibility (M = 2.41, SD = 0.38). CONCLUSIONS: Siyakhana was associated with reductions in CHW SU stigma in the context of HIV/TB care, with promising implementation outcomes. Findings will inform a larger randomized trial evaluating the effectiveness and implementation of Siyakhana and examine whether shifting CHW stigma improves patient-level health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05282173. Registered on 7 March 2022.