We compared the activities of linezolid (25 mg/kg of body weight, administered intraperitoneally every 8 h) and of vancomycin (25 mg/kg of body weight, administered intraperitoneally every 8 h) in a rat model of vanA vancomycin-resistant Enterococcus faecium experimental endocarditis. Results were expressed as median log(10) CFU per gram of vegetation after 3 days of treatment. The median log(10) CFU per gram of vegetation was 10.1 among 7 untreated control animals, 10.2 among 9 vancomycin-treated animals, and 7.9 among 10 linezolid-treated animals. Linezolid treatment was more active (P < 0.05) than vancomycin treatment or no treatment.