BACKGROUND/AIMS: Tuberculosis remains one of the leading causes of death from an infectious disease globally. Both choices of outcome definitions and approaches to handling events happening post-randomisation can change the treatment effect being estimated, but these are often inconsistently described, thus inhibiting clear interpretation and comparison across trials. METHODS: Starting from the ICH E9(R1) addendum's definition of an estimand, we use our experience of conducting large Phase III tuberculosis treatment trials and our understanding of the estimand framework to identify the key decisions regarding how different event types are handled in the primary outcome definition, and the important points that should be considered in making such decisions. A key issue is the handling of intercurrent (i.e. post-randomisation) events (ICEs) which affect interpretation of or preclude measurement of the intended final outcome. We consider common ICEs including treatment changes and treatment extension, poor adherence to randomised treatment, re-infection with a new strain of tuberculosis which is different from the original infection, and death. We use two completed tuberculosis trials (REMoxTB and STREAM Stage 1) as illustrative examples. These trials tested non-inferiority of new tuberculosis treatment regimens versus a control regimen. The primary outcome was a binary composite endpoint, 'favourable' or 'unfavourable', which was constructed from several components. RESULTS: We propose the following improvements in handling the above-mentioned ICEs and loss to follow-up (a post-randomisation event that is not in itself an ICE). First, changes to allocated regimens should not necessarily be viewed as an unfavourable outcome; from the patient perspective, the potential harms associated with a change in the regimen should instead be directly quantified. Second, handling poor adherence to randomised treatment using a per-protocol analysis does not necessarily target a clear estimand; instead, it would be desirable to develop ways to estimate the treatment effects more relevant to programmatic settings. Third, re-infection with a new strain of tuberculosis could be handled with different strategies, depending on whether the outcome of interest is the ability to attain culture negativity from infection with any strain of tuberculosis, or specifically the presenting strain of tuberculosis. Fourth, where possible, death could be separated into tuberculosis-related and non-tuberculosis-related and handled using appropriate strategies. Finally, although some losses to follow-up would result in early treatment discontinuation, patients lost to follow-up before the end of the trial should not always be classified as having an unfavourable outcome. Instead, loss to follow-up should be separated from not completing the treatment, which is an ICE and may be considered as an unfavourable outcome. CONCLUSION: The estimand framework clarifies many issues in tuberculosis trials but also challenges trialists to justify and improve their outcome definitions. Future trialists should consider all the above points in defining their outcomes.