Summary

RR/MDR-TB is a major public heath challenge in Vietnam, with nearly 10,000 incident cases estimated annually. Whether RR-TB burden reflects ongoing transmission of resistant strains or repeated de novo acquisition of resistance during treatment has direct implications for control strategies but has been difficult to quantify reliably. This study addresses this gap through comprehensive, city-wide sampling and whole-genome sequencing of RR-TB in Ho Chi Minh City from 2020 to 2024. By integrating phylogenetic inference with clinical histories and correcting for incomplete sampling using a novel simulation-extrapolation framework, we demonstrate that 72–87% of RR-TB is attributable to transmission. We further reconstruct four decades of resistance emergence, showing that early events in the 1980s seeded transmission clades that persist city-wide today, and that new resistance continues to emerge despite programmatic safeguards. While our findings frame transmission as the primary driver of RR-TB in Vietnam, a substantial and potentially preventable fraction still arises from acquired resistance.