Once-weekly rifapentine 600 mg plus isoniazid (INH) during the continuation phase treatment of tuberculosis is associated with a relapse rate higher than that of twice-weekly rifampin plus INH. The safety and tolerability of higher rifapentine doses need to be determined. We conducted a prospective, randomized, double-blind trial of rifapentine at three doses (600, 900, and 1,200 mg) plus INH 15 mg/kg once weekly in the continuation phase treatment of culture-positive tuberculosis in 150 human immunodeficiency virus-seronegative adults. Outcome measures were discontinuation of therapy for any reason and adverse events on therapy. Treatment was discontinued in 3 of 52 (6%), 2 of 51 (4%), and 3 of 47 (6%) in the rifapentine 600-, 900-, and 1,200-mg treatment arms, respectively. Only one discontinuation, in the rifapentine 1,200-mg arm, was due to an adverse event possibly associated with study therapy. There was a trend toward more adverse events, possibly associated with study therapy, in the highest-dose arms (p = 0.051). Rifapentine 900-mg, once-weekly dosing appears to be safe and well tolerated and is being evaluated in Phase III efficacy trials of treatment of latent tuberculosis. Further evaluation of the safety and tolerability of rifapentine 1,200 mg is warranted.