BACKGROUND: Drivers of tuberculosis (TB) transmission in India, the country estimated to carry a quarter of the world's burden, are not well studied. We conducted a genomic epidemiology study to compare epidemiological success, host factors, and drug resistance among the 4 major Mycobacterium tuberculosis (Mtb) lineages (L1-L4) circulating in Pune, India. METHODS: We performed whole-genome sequencing (WGS) of Mtb sputum culture-positive isolates from participants in two prospective cohort studies and predicted genotypic susceptibility using a validated random forest model. We compared lineage-specific phylogenetic and time-scaled metrics to assess epidemiological success. RESULTS: Of the 612 isolates that met sequence quality criteria, Most were L3 (44.6%). The majority (61.1%) of multidrug-resistant isolates were L2 (P < .001) and L2 demonstrated a higher rate and more recent resistance acquisition. L4 and/or L2 demonstrated higher clustering and time-scaled haplotypic density (THD) compared to L3 and/or L1, suggesting higher epidemiological success. L4 demonstrated higher THD and clustering (odds ratio, 5.1 [95% confidence interval, 2.3-12.3]) in multivariate models controlling for host factors and resistance. CONCLUSIONS: L2 shows a higher frequency of resistance, and both L2 and L4 demonstrate evidence of higher epidemiological success than L3 or L1 in Pune. Contact tracing around TB cases and heightened surveillance of TB DR in India is a public health priority.