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There is substantial state-to-state heterogeneity in tuberculosis (TB) in the United States; better understanding this heterogeneity can inform effective response to TB at the state level, the level at which most TB control efforts are coordinated.To characterize drivers of state-level heterogeneity in TB epidemiology in the four U.S. states that bear half the country's TB burden: California, Florida, New York, and Texas.We constructed an individual-based model of TB in the four U.S. states and calibrated the model to state-specific demographic and age- and nativity-stratified TB incidence data. We used the model to infer differences in natural history of TB and in future projections of TB.We found that differences in both demographic makeup (particularly the size and composition of the foreign-born population) and TB transmission dynamics contribute to state-level differences in TB epidemiology. The projected median annual rate of decline in TB incidence in the next decade was substantially higher in Texas (3.3%; 95% range, −5.6 to 10.9) than in California (1.7%; 95% range, −3.8 to 7.1), Florida (1.5%; 95% range, −7.4 to 14), and New York (1.9%; 95% range, −6.4 to 9.8). All scenarios projected a flattening of the decline in TB incidence by 2025 without additional resources or interventions.There is substantial state-level heterogeneity in TB epidemiology in the four states, which reflect both demographic factors and potential differences in the natural history of TB. These differences may inform resource allocation decisions in these states.