BACKGROUND: Up to fifty percent of microbiologically cured tuberculosis (TB) patients may be left with permanent, moderate or severe pulmonary function impairment. Very few studies have systematically examined pulmonary outcomes in patients to understand the pathophysiologic basis and long-term socio-economic consequences of this injury. The planned multi-country, multi-centre observational TB cohort study, aims to advance the understanding of the clinical, microbiological, immunological and socio-economic risk factors affecting long-term outcome of pulmonary TB. It will also determine the occurrence of reversible and irreversible socio-economic consequences to patients, their households and the health sector related to pulmonary TB disease and its treatment. METHODS: We will enrol up to 1.600 patients with drug sensitive and multidrug-resistant pulmonary TB who are treated according to the local standard of care by the respective National TB Program. Recruitment is taking place at the time of TB diagnosis at four African study clinics located in The Gambia, Mozambique, South Africa and Tanzania. The primary outcome is the proportion of TB patients with severe lung impairment measured by spirometry at 24 months after TB treatment initiation. Biological samples, including sputum, urine and blood, for studying host- and pathogenic risk factors will be collected longitudinally and examined in a nested case-control fashion. A standardized quality of life questionnaire will be used together with a novel version of WHO's generic patient cost instrument which has been adapted for the longitudinal study design. DISCUSSION: This study is an integral part of an overall strategy to fill a knowledge gap needed to improve TB treatment outcomes globally. The main scientific goal is to identify the major pathogenic mechanisms associated with poor TB treatment outcomes, so that such pathways can be interrupted to avert long term TB sequelae. National as well as supra-national stakeholders and decision makers have been integrated early in the study planning process to inform future treatment guidelines and national health policies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03251196 , August 16, 2017.