 The investigators have initiated a research program to evaluate the compliance, safety, costs and effectiveness of 4RIF for the treatment of LTBI. In the initial study of 116 patients, 4RIF was associated with significantly higher completion rates 90 vs 70. The second phase of this study, conducted in Montreal, Toronto, Kingston, Saskatoon, Calgary, and Edmonton, plus Brazil and Saudi Arabia, compared the rates of serious adverse events SAE with the two regimens. These were adjudicated by an independent three member review panel, blinded to study drug. In this phase, among 420 subjects randomized to 4RIF overall rate of Grade 3-4 SAE was 2.4 compared to 5.6 among the 427 taking 9INH p.02. Grade 3-4 hepatotoxicity was very significantly lower 0.7 vs 3.8; p.003. Health system costs were also significantly lower, and completion rates significantly higher with 4RIF Therefore the conditions have been met to conduct the first randomized trial that will compare effectiveness of 4RIF and 9INH in preventing tuberculosis. Among the moderate to high risk subjects that will be eligible, the anticipated cumulative risk of active TB, if untreated, will be at least 3 during a follow-up of 28 months after randomization. We anticipate 50 completion rate with 9INH, providing an effectiveness of 45 based on known efficacy of 90. To detect superior effectiveness of 4RIF, assuming 80 completion, and 10 loss in follow-up, plus accounting for cluster randomization of household contacts we would require enrolment of 3283 subjects per arm, or a total of 6,566 subjects. This is reduced to 5720, because the 847 already randomized in Phase 2, were randomized, treated and followed for 28 months post-randomization to determine occurrence of active TB - using the same methods described in this proposal. 