Overview: This proposal directly addresses one of the most critical public health challenges impacting the health and survival of people with HIV (PWH) and/or tuberculosis (TB) in South Africa (SA): smoking. Background/Significance: Smoking reduces antiretroviral therapy (ART) adherence among PWH, compromising HIV treatment outcomes, and is linked to lower TB treatment adherence among patients newly diagnosed with TB, as well as to TB treatment failure, loss to follow up during treatment, and death during or after treatment. Preliminary studies: In this R34 application, we propose to develop a smoking cessation intervention tailored to the SA context that improves disease outcomes for both HIV and TB, bringing together our experience from two overlapping areas of research. First, we completed a randomized controlled trial (RCT) that established initial efficacy, feasibility, and acceptability of a cognitive behavioral therapy smoking cessation intervention (QUIT) for PWH in the US, which increased biologically-verified abstinence rates at 6 months compared to controls.1 Second, we recently completed an efficacy/effectiveness trial of a cognitive behavioral ART adherence intervention, which successfully increased HIV treatment adherence and reduced viral load among PWH in Cape Town.2 Therefore, our US- and SA-based investigator team has expertise in smoking cessation treatment development for individuals with chronic disease and in adapting evidence-based, cognitive behavioral strategies for treatment adherence in a low-resource setting. Approach: We now propose to extend this body of work by developing QUIT-AD, a novel intervention which will integrate our QUIT program with cognitive behavioral strategies that have been culturally adapted to improve treatment adherence among PWH and/or TB in SA. To do so, we will: more thoroughly understand (a) barriers to smoking cessation among adults with HIV and/or TB and (b) barriers to TB treatment adherence among adults with TB who use tobacco (Aim 1); adapt the QUIT protocol, adding and removing content as appropriate based on the formative data, and conduct a small proof-of-concept open trial (n = 5; Aim 2); and assess the feasibility and acceptability of the intervention in a pilot RCT to be task shifted to lay counselors (Aim 3). Secondary outcomes of the RCT will be biologically-verified point prevalence tobacco abstinence, number of cigarettes smoked in the past week, and favorable HIV/TB treatment outcome at 6 months. Outcomes/next steps: These aims will lay the groundwork for a full-scale, hybrid effectiveness/implementation trial which could change the smoking cessation treatment landscape in SA, provide an empirically supported program for PWH and/or TB, and serve as a model for future work to sustain smoking abstinence among individuals with chronic diseases in resource-limited settings.