Rationale: Recent studies demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard daily short-course regimen of rifampin, isoniazid and pyrazinamide produces stable cure in 12 wks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and isoniazid to rifapentine-based regimens. Objectives: We compared bactericidal activity and treatment shortening potential between regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily. Methods: Using a mouse model of tuberculosis we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure. Measurements and Main Results: After 4 weeks treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, isoniazid and pyrazinamide. By 8 weeks treatment all mice receiving the moxifloxacin-based regimens were lung culture negative whereas those mice receiving the isoniazid-based regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, isoniazid and pyrazinamide relapsed after 12 weeks treatment. Conclusions: These results suggest that regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis.