OBJECTIVES: World Health Organization recommends a 7-drug 9-11-month rifampicin-resistant tuberculosis (RR-TB) short treatment regimen (STR). To reduce the pill burden, we assessed the safety and effectiveness of a 5-drug 9-11-month modified STR (mSTR). METHODS: Prospective cohort study of an all-oral mSTR (comprising bedaquiline, levofloxacin, linezolid [LZD], clofazimine, and/or pyrazinamide) for patients with RR-TB without confirmed fluoroquinolone resistance, enrolled in Vietnam between 2020-2021. RESULTS: A total of 108 patients were enrolled in this study. Overall, 63 of 74 (85%) achieved culture conversion at 2 months. Of 106 evaluated, 95 (90%) were successfully treated, six (6%) were lost-to-follow-up, one (1%) died, and four (4%) had treatment failure, including three with permanent regimen change owing to adverse events (AE) and one with culture reversion. Of 108, 32 (30%) patients encountered at least one AE. Of 45 AEs recorded, 13 (29%) were serious (hospitalization, life threatening, or death). The median time to AE was 3 months (IQR: 2-5). A total of 26 AEs led to regimen adaptation: either dose reduction (N = 1), drug temporary interruption (N = 19), or drug permanent discontinuation (N = 6, 4 attributed to LZD). CONCLUSION: The high treatment success of 5-drug mSTR might replace the 7-drug regimen in routine care. AEs were frequent, but manageable in most patients. Active AEs monitoring is essential, particularly when using LZD throughout.