The goal of this investigator-initiated, clinical trial application is to conduct a randomized trial comparing treatment success rates and safety of daily rifapentine and isoniazid (1HP) and 3 months of weekly rifapentine and isoniazid (3HP) TB preventive therapy (TPT) regimens in high-risk patients without HIV infection. We will 1) compare treatment success with good adherence, documented by self-report, pill count, and pharmacologic monitoring, of 1HP compared with 3HP in HIV-uninfected adults and adolescents at increased risk of TB and 2) compare the safety of 1HP vs 3HP in this population. We hypothesize that successful treatment with 1HP will be superior to 3HP, and that the safety and tolerability of 1HP will be superior to 3HP. We will also compare the cost-effectiveness of 1HP and 3HP using a societal approach, modeling the incremental cost-effectiveness of 1HP vs 3HP, 6H, and no treatment. The results of this trial will be extremely valuable for establishing global and US guidelines for use of 1HP in HIV-negative people.