Someβ-lactam antibiotics are active in vitro againstMycobacterium tuberculosis.There are anecdotal reports of successful treatment of tuberculosis caused by multiple-drug-resistant strains ofM. tuberculosiswith regimens that included amoxicillin/clavulanate. Reduction ofM. tuberculosisin the sputum of patients with pulmonary tuberculosis during administration of amoxicillin/clavulanate was measured by a quantitative culture method to determine the activity in vivo. Patients were randomized to receive isoniazid, ofloxacin, or amoxicillin/clavulanate for 7 days. Isoniazid was the most effective agent, reducingM. tuberculosisafter 2 days at a mean rate (± standard deviation) of 0.60 ± 0.30 log10 cfu/mL per day, compared with 0.32 ± 0.05 and 0.34 ± 0.03 for ofloxacin and amoxicillin/clavulanate, respectively. The early bactericidal activity of amoxicillin/clavulanate was comparable to that reported for antituberculous agents other than isoniazid. Further studies ofβ-lactam antibiotics with in vitro activity againstM. tuberculosisare warranted to define their role in treatment of tuberculosis.