Abstract There is an urgent need to implement effective tobacco cessation interventions in HIV care programs in low- and middle-income countries (LMICs) where most tobacco users and people with HIV live. India is an important setting in which to test tobacco cessation interventions with an estimated 275 million tobacco users and 2 million people living with HIV (PWH). Effective medications and behavioral interventions have not been well tested in HIV care settings in LMICs. In high income settings, Positively Smoke Free (PSF), a theory- based behavioral intervention, has demonstrated efficacy among PWH and been adapted for mobile phone delivery (PSF-M). Mobile health interventions offer scalability and may be more effective among PWH than face-to-face. Varenicline is the cessation medication with the strongest evidence of efficacy in PWH but achieving sufficient adherence to sustain long-term success is a challenge. We propose to combine the two most promising cessation interventions among PWH, varenicline and PSF-M, enhanced with varenicline adherence support. They will be tested at the Voluntary Health Services (VHS) Infectious Disease Medical Center, Chennai Antiviral Research and Treatment Clinical Research Site, where 24% of patients new to HIV care are current smokers or dual users of smoked and smokeless tobacco and 83% own mobile phones. In this setting we propose the following specific aims: (1) To demonstrate the effectiveness of an integrated intervention combining varenicline plus mobile behavioral treatment among tobacco users in HIV care on biochemically verified tobacco abstinence at 24 weeks compared to a standard care control; (2): To evaluate the implementation processes of the integrated intervention in an LMIC HIV practice; and (3): To measure the costs and cost-effectiveness of an integrated intervention with varenicline and PSF-M. To accomplish these aims, PSF-M will be adapted to the VHS context and novel content about smokeless tobacco and medication adherence self-efficacy will be added. A randomized two-arm trial will compare the combination of varenicline and PSF-M to a standard care control. We will evaluate implementation processes within HIV care workflows including acceptability, appropriateness, feasibility and costs and conduct cost-effectiveness analysis to assess the clinical impact and value of the integrated intervention if scaled-up. The work proposed is responsive to the specific interests in RFA-CA-20-037 by testing the effectiveness of tobacco cessation interventions with demonstrated efficacy in other settings and adapted for an LMIC context, evaluating the implementation process from multiple stakeholder perspectives in an HIV care practice, and assessing the clinical impact and value of the integrated intervention if implemented at scale. The successful completion of this work will move the field forward by advancing our understanding of the effectiveness of an integrated tobacco cessation intervention ...