BACKGROUND: Evidence shows that isoniazid preventive therapy (IPT) reduces tuberculosis (TB) incidence among people with human immunodeficiency virus (HIV) with additive benefit beyond antiretroviral therapy alone, but its effectiveness in settings with high multidrug-resistant TB (MDR-TB) burden is unclear. We assessed the relationship between IPT and TB incidence among people with HIV (PWH) in Ukraine, a high-burden (32.6%) MDR-TB setting, and whether its effectiveness is maintained among virologically suppressed persons. METHODS: We analyzed national surveillance data for HIV and TB collected between 2018 and 2022. Complete IPT (n = 40 733) was defined as receipt of ≥146 days of therapy and no IPT (n = 91 022) as <28 days of therapy. We modeled TB incidence and death using Poisson regression adjusting for covariates related to receipt of IPT and TB incidence. The secondary outcome was multidrug resistance, and sensitivity analyses explored the influence of virologic suppression. RESULTS: Of 131 755 PWH who met inclusion criteria, 9089 (5.5%) died. Unadjusted TB incidence was 1.91 cases per 100 person-years in the No IPT group and 1.01 cases per 100 person-years in the Complete IPT group (adjusted incidence rate ratio [aIRR], 1.99). MDR-TB occurred in 29.1% and 30.7% of TB cases in the Complete and No IPT groups, respectively. Among virologically suppressed PWH, persons with no IPT had a higher TB incidence (aIRR, 1.38) than those who completed IPT. CONCLUSIONS: Completing IPT as part of a public health intervention can significantly reduce TB incidence among PWH, even in settings with high-burden MDR-TB and among the virologically suppressed.