BACKGROUND: Throughout the last decade, tuberculosis (TB) treatment success has not surpassed 90%, the global target. The impact of mobile health interventions (MHIs) on TB treatment outcomes is unknown, especially in low- and middle-income countries (LMICs). MHIs, including interactive voice response technology (IVRT), may enhance adherence and retention in the care of patients with tuberculosis and improve TB treatment outcomes. This study seeks to determine the impact of IVRT-based MHI on TB treatment success (treatment completion and cure rates) in patients with TB receiving care at five public health facilities in Uganda. METHODS: We used a theory-based and human-centered design (HCD) to adapt an already piloted software to design "Call for life-TB" (CFL-TB), an MHI that utilizes IVRT to deliver adherence and appointment reminders and allows remote symptom reporting. This open-label, multicenter, randomized controlled trial (RCT), with nested qualitative and economic evaluation studies, will determine the impact of CFL-TB on TB treatment success in patients with drug-susceptible TB in Uganda. Participants (n = 274) at the five study sites will be randomized (1:1 ratio) to either control (standard of care) or intervention (adherence and appointment reminders, and health tips) arms. Multivariable regression models will be used to compare treatment success, adherence to treatment and clinic appointments, and treatment completion at 6 months post-enrolment. Additionally, we will determine the cost-effectiveness, acceptability, and perceptions of stakeholders. The study received national ethical approval and was conducted in accordance with the international ethical guidelines. DISCUSSION: This randomized controlled trial aims to evaluate interactive voice response technology in the context of resource-limited settings with a high burden of TB and high illiteracy rates. The software to be evaluated was developed using HCD and the intervention was based on the IMB model. The software is tailored to the local context and is interoperable with the MHI ecosystem. The HCD approach ensures higher usability of the MHI by integrating human factors in the prototype development. This research will contribute towards the understanding of the implementation and impact of the MHI on TB treatment outcomes and the health system, especially in LMICs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04709159 . Registered on January 14, 2021.