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RATIONALE: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. OBJECTIVES: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. METHODS: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA(CFU0–14)) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. MEASUREMENTS AND MAIN RESULTS: Sixty participants enrolled. Median EBA(CFU0–14) counts (2.5th–97.5th percentiles) were 0.22 (0.12–0.33), 0.12 (0.057–0.21), 0.059 (0.033–0.097), and 0.053 (0.035–0.081); TTP increased by 0.34 (0.21–0.75), 0.11 (0.052–0.37), 0.094 (0.034–0.23), and 0.12 (0.04–0.41) (log(10) h), for arms C–F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. CONCLUSIONS: Bactericidal activity was greater with the World Health Organization–recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).