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We model the epidemiological impact of providing isoniazid preventive therapy (IPT) to South African adolescents, among whom HIV prevalence is low, latent tuberculosis (TB) prevalence is high, and school-based programs may enable population-level coverage.We simulate a dynamic compartmental model of age-structured HIV and TB coepidemics in South Africa. HIV dynamics are modeled by infection status, CD4+ cell count, and antiretroviral therapy; TB dynamics are modeled by disease stage, diagnosis, treatment, and IPT status. We analyze the effects of continuous IPT coverage among adolescents from 5 (baseline) to 90%.Our model is calibrated to WHO and the Joint United Nations Programme on HIV/AIDS epidemiological estimates. In simulations, increasing IPT coverage to 50% among adolescents reduced active TB incidence by 5–34%. Increasing coverage to 90% led to a 9–40% reduction in active TB incidence. Expanded IPT access causes TB incidence to decline in the general population of HIV-positive individuals, as well as in adult HIV-positive individuals.Targeting IPT to a secondary school population with high latent TB prevalence and low-HIV prevalence, in which risk of false-negative diagnosis of active TB is low and IPT benefits are more established, could have substantial benefits to adolescents and spillover benefits to the adult population.