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Extending the duration of isoniazid preventive therapy (IPT) among people living with HIV (PLHIV) may improve its effectiveness at both individual and population levels, but could also increase selective pressure in favor of isoniazid-resistant tuberculosis (TB) strains. The objective of this study was to determine the relative importance of these two effects.Transmission dynamic model.We created a mathematical model of TB transmission incorporating HIV incidence and treatment, mixed strain latent TB infections, and four different phenotypes of TB drug resistance (pan-susceptible, isoniazid monoresistant, rifampicin monoresistant, and multidrug resistant). We used this model to project the effects of IPT duration on the incidence of isoniazid-sensitive and isoniazid-resistant TB as well as mortality among PLHIV. We evaluated the sensitivity of our baseline model, which was calibrated to data from Botswana, to different assumptions about the future trajectory of the TB epidemic.Our model suggests that, in the context of a declining TB epidemic such as that currently observed in Botswana, the incidence and mortality benefits of continuous IPT for PLHIV are likely to outweigh the potential resistance risks associated with long-duration IPT. However, should TB epidemics fail to remain in control, as was observed during the initial emergence of HIV, the selective pressure imposed by widespread use of continuous IPT on isoniazid-resistant TB incidence may erode its initial benefits.Resistance concerns are likely insufficient to rule out use of continuous IPT when coupled with effective TB treatment, case finding, and HIV control.