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Background. The oxazolidinone PNU-100480 is superior to linezolid against experimental murine tuberculosis. Two metabolites contribute to but do not fully account for its superiority. This study examined the safety, tolerability, pharmacokinetics, and mycobactericidal activity of single ascending doses of PNU-100480. Methods. Nineteen healthy volunteers received 2 escalating single oral doses (35–1500 µg) of PNU-100480 or placebo. Eight subjects received 4 daily doses of 300 mg of linezolid. Drug concentrations and bactericidal activity against Mycobacterium tuberculosis in whole-blood bactericidal culture were measured. Results. All doses were safe and well tolerated. PNU-100480 doses to 1000 mg were well absorbed and showed approximately proportional increases in exposures of parent and metabolites. The geometric mean maximal concentrations of PNU-100480, PNU-101603, and PNU-101244 (sulfoxide and sulfone metabolites) at 1000 mg were 839, 3558, and 54 ng/mL, respectively. The maximal whole-blood bactericidal activity (−0.37 ± .06 log/day) occurred at combined PNU levels ⩾2 times the minimum inhibitory concentration. The observed geometric mean maximal concentration for linezolid was 6425 ng/mL. Its maximal whole-blood bactericidal activity also occurred at ⩾2 times the minimum inhibitory concentration, but it was only −0.16 ± .05 log/day (P<.001). Neither drug showed enhanced activity at higher concentrations. Conclusions. Single doses of PNU-100480 to 1000 mg were well tolerated and exhibited antimycobacterial activity superior to 300 mg of linezolid at steady state. Additional studies are warranted to define its role in drugresistant tuberculosis. Clinical trial registration ClinicalTrials.gov identifiers NCT00871949 and NCT00990990.