Background —The potential epidemiological impact of isoniazid preventive therapy (IPT), delivered at levels that could be feasibly scaled up among people living with HIV (PLHIV) in modern, moderate-burden settings, remains uncertain. Methods — We used routine surveillance and implementation data from a cluster-randomized trial of IPT among HIV-infected clinic patients with good access to antiretroviral therapy in Rio de Janeiro, Brazil, to populate a parsimonious transmission model of TB/HIV. We modeled IPT delivery as a constant process capturing a proportion of the eligible population every year. We projected feasible reductions in tuberculosis (TB) incidence and mortality in the general population and among PLHIV specifically at the end of five years after implementing an IPT program. Results — Data on time to IPT fit an exponential curve well, suggesting that IPT was delivered at a rate covering 20% (95% confidence interval: 16%, 24%) of the 2,500 eligible individuals each year. By the end of year 5 after modeled program roll-out, IPT had reduced TB incidence by 3.0% (95% uncertainty range, UR: 1.6%, 7.2%) in the general population and by 15.6% (95%UR: 15.5%, 36.5%) among PLHIV. Corresponding reductions in TB mortality were 4.0% (95%UR: 2.2%, 10.3%) and 14.3% (14.6%, 33.7%). Results were robust to wide variations in parameter values on sensitivity analysis. Conclusions — TB screening and IPT delivery can substantially reduce TB incidence and mortality among PLHIV in urban, moderate-burden settings. In such settings, IPT can be an important component of a multi-faceted strategy to feasibly reduce the burden of TB in PLHIV.