Rationale: The optimal approach for reducing tuberculosis relapse is open. Objectives: We examined the possibility of reducing relapse by increasing dosing schedules. Methods:We conducted a systematic review of published clinical trials involving adult cohorts with pulmonary tuberculosis treated by six-month rifamycin-containing regimens,which were grouped under seven categories ordered by dosing schedules. Assuming cavitation and positive two-month culture were the driving forces for relapse, a static deterministic model apportioned observed numbers with and without relapse in each cohort into eight subgroups. Combining subgroups stratified by cavitation, two-month culture and regimens enabled estimation of adjusted relapse risks. Chi-squared tests for trend and logistic regression analysis examined the relationship between relapse and dosing schedules. Results:We identified 200 cases of bacteriological relapse out of 5208 patients in 32 cohorts. A logistic risk model showed a significant dose-response relationship between dosing schedules and relapse with the following odds (95% confidence intervals) of relapse relative to daily regimens: 1.6(0.6-4.1) for daily initial phase (IP) plus thrice-weekly continuation phase (CP); 2.8(1.3-6.1) for daily IP plus twice-weekly CP; 2.8(1.4-5.7) for thrice-weekly; 5.0(2.4-10.5) for daily IP plus once-weekly rifapentine; and 7.1(3.3-15.3) for thrice-weekly IP plus once-weekly rifapentine. In the presence of cavitation, only six-month daily or daily IP plus thrice-weekly CP attained best-estimated relapse risks below 5%; they reached 6% when two-month culture was also positive. Conclusions: Cavitary tuberculosis is best treated with six-month regimens comprising daily IP and thrice-weekly CP, which may be extended when two-month culture is positive.