•Triple-dose rifampicin is known to be safe for tuberculosis treatment.•Triple-dose isoniazid is known to be safe for tuberculosis treatment.•A triple dose of both rifampicin and isoniazid causes excess drug-related adverse events.•Treatment for six months throughout with four first-line drugs, all at a normal dose, is safe. High-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. The primary objective of the TRIple-DOse RE-treatment (TRIDORE) study is to determine whether a 6-month firstline regimen with triple dose of both R and H (intervention arm; 6R3H3ZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with R-susceptible (Rs) recurrent tuberculosis (TB). TRIDORE is an ongoing pragmatic open-label multi-stage randomized clinical trial. Between March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6R3H3ZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and the median age (interquartile range) was 37 (30-48) years. The median body mass index at enrollment was 18.1 (16.3-19.7) kg/m2. Drugrelated severe adverse events (AEs) (grade III-V) were significantly more frequent when 6R3H3ZE was used (5/62 vs 0/65, P = 0.03, difference weighted for site 8% 95% confidence interval: 1.0,14.3). The Data and Safety Monitoring Board recommended publishing our interim safety data analysis. We show that the combination of triple-dose R with triple-dose H in a re-treatment regimen for patients with Rs-TB causes excess drug-related AEs.