Increasing resistance among enterococci poses a considerable therapeutic problem. In this study, we evaluated the comparative in vitro activity of two investigational oxazolidinone antibiotics, eperezolid and linezolid, versus clinical isolates of multidrug-resistant enterococci. One hundred isolates (16 Enterococcus faecalis, 69 E. faecium, 10 E. gallinarum, 2 E. casseliflavus, 1 E. avium, 1 E. hirae, and 1 E. raffinosus) evaluated were collected from diverse geographic areas in North America and Europe from 1991 to 1995. Eperezolid MIC50 and MIC90 were 1.0 microgram/mL and 2.0 micrograms/mL (1.0-2.0 micrograms/mL range). Linezolid MIC50 and MIC90 were 2.0 micrograms/mL and 2.0 micrograms/mL (0.5-2.0 micrograms/mL range), respectively. MICs were the same at 10(3) CFU/mL and 10(8) CFU/mL initial inoculum. In time-kill experiments using 10 strains and concentrations of 4 micrograms/mL, 8 micrograms/mL, and 16 micrograms/mL (achievable serum concentrations) of eperezolid and linezolid there was a 2 log10 reduction of growth for 2 of 10 isolates tested using eperezolid and a 1 log10 reduction for 50% of isolates with both agents. There was indifferent bactericidal killing when either oxazolidinone was combined with gentamicin, ampicillin, or streptomycin for isolates lacking these resistances. This study demonstrates these oxazolidinone agents to have excellent in vitro activity versus multidrug-resistant enterococci.