Objective: Compare the effectiveness, tolerability, and safety of three months of weekly rifapentine plus isoniazid under direct observation (3HP) vs. 9 months of daily isoniazid (9H) in HIV-infected persons. Design: Prospective, randomized, open-label non-inferiority trial. Setting: U.S., Brazil, Spain, Peru, Canada, and Hong Kong. Participants: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases. Intervention: 3HP vs. 9H. Main Outcome Measures: The effectiveness endpoint was tuberculosis; the non-inferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation due to adverse drug reaction. Results: Median baseline CD4+ counts were 495 (IQR:389–675) and 538 (IQR:418–729) cells/mm3 in the 3HP and 9H arms, respectively (P=0.09). In the modified intention to treat analysis, there were two tuberculosis cases among 206 persons (517 person-years (p-y) of followup) in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01% vs. 3.50% in the 3HP and 9H arms, respectively (rate difference: −2.49%; upper bound of the 95% confidence interval (CI) of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P<0.001), and drug discontinuation due to an adverse drug reaction was similar (3% vs. 4%; P=0.79) in 3HP and 9H, respectively. Conclusions: Among HIV-infected persons with median CD4+ count of approximately 500 cells/mm3 , 3HP was as effective and safe for treatment of latent M. tuberculosis infection as 9H, and better tolerated.