BACKGROUND: South Africa has achieved drug-susceptible TB (DS-TB) treatment success of only 77% among people with new and previously treated TB. Alternative approaches are required to improve medication adherence and treatment completion to limit transmission, TB relapse and the development of resistance. This study aims to implement and evaluate the use of adherence medication monitors (Wisepill evriMED 1000) with a differentiated response to patient care, among DS-TB patients in three provinces of South Africa. METHODS: In total, 18 public health clinics across three provinces were selected. Clinics were randomised to intervention or standard of care clinics. In each clinic, approximately 145 DS-TB patients are being enrolled to reach a total of 2610. All patients have their daily adherence monitored using medication monitors. In the intervention arm, patients are receiving medication monitor reminders and differentiated care in response to adherence data. This weekly review of daily real-time monitoring will be undertaken from a central database. The differentiated care model includes automated SMS reminders with a missed dose, research staff-initiated phone call to the patient with a second or third missed dose, a home visit if four or more doses are missed, and motivational counselling if four or more doses are missed repeatedly. Fidelity of the intervention will be measured through process evaluation. Patients in control clinics will receive medication monitors for adherence tracking, standard of care TB education, and normal clinic follow-up procedures. The primary outcome is the proportion of patients by arm with >80% adherence, as measured by the medication monitor. The feasibility and acceptability of the intervention will be assessed by in-depth interviews with patients, stakeholders, and study staff. A cost effectiveness analysis of the intervention and standard of care clinics will be conducted. SIGNIFICANCE: This trial will provide evidence for the use of an intervention, including medication monitors and differentiated care package, to improve adherence to TB treatment. Improved adherence should also improve TB treatment completion rates, thus reducing loss to follow-up rates, and TB relapse among people with TB. The intervention is intended to ultimately improve overall TB control and reduce TB transmission in South Africa. TRIAL REGISTRATION: Pan African Trial Registry PACTR201902681157721 . Registered on 11 February 2019.