ObjectiveIdentifying the risk factors for deaths during tuberculosis (TB) treatment is important for achieving the vision of India's National Strategic Plan of ‘Zero Deaths’ by 2025. We aimed to determine the proportion of deaths during TB treatment and its risk factors among smear positive pulmonary TB patients aged more than 15 years. Study designWe performed a cohort study using data collected for RePORT India Consortium (Regional Prospective Observational Research in Tuberculosis). SettingRevised TB Control Program (RNTCP) in three districts of South India. ParticipantsThe cohort consisted of newly diagnosed drug sensitive patients enrolled under the Revised National TB Control Program during 2014–2018 in three districts of southern India. Information on death was collected at homes by trained project staff. Primary outcome measuresWe calculated ‘all-cause mortality’ during TB treatment and expressed this as a proportion with 95% confidence interval (CI). Risk factors for death were assessed by calculating unadjusted and adjusted relative risks with 95% CI. ResultsThe mean (SD) age was of the 1167 participants was 45 (14.5) years and 79% of them were males. Five participants (0.4%) were HIV infected. Among the males, 560 (61%) were tobacco users and 688 (75%) reported consuming alcohol. There were 47 deaths (4%; 95% CI 3.0–5.3) of which 28 deaths (60%) occurred during first two months of treatment. In a bi-variable analysis, age of more than 60 years (RR 2.27; 95%CI: 1.24–4.15), male gender (RR 3.98; 95% CI: 1.25–12.70), alcohol use in last 12 months (RR 2.03; 95%CI: 1.07–3.87), tobacco use (RR 1.87; 95%CI: 1.05–3.36) and severe anaemia (RR 3.53: 95%CI: 1.34–9.30) were associated with a higher risk of death. In adjusted analysis, participants with severe anaemia (<7gm/dl) had 2.4 times higher risk of death compared to their counterparts. ConclusionThough deaths during TB treatment was not very high, early recognition of risk groups and targeted interventions are required to achieve zero TB deaths.