Currently, there exist few satisfactory alternatives to vancomycin for therapy of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. We employed a rat model of aortic valve endocarditis to assess the potential efficacy of evernimicin (SCH 27899) compared with vancomycin against infection with a strain susceptible to both agents (MICs of 0.25 and 0.50 µg/ml, respectively). Infected animals were assigned to one of three groups: controls (no treatment), evernimicin at 60 mg/kg of body weight by intravenous (i.v.) infusion once daily, or vancomycin at 150 mg/kg of body weight per day by continuous i.v. infusion. Therapy was administered for 5.5 days. At the start of therapy, colony counts in vegetations were 6.63 ± 0.44 log₁₀ CFU/g. In both treatment groups, bacterial density within vegetations was significantly reduced in comparison with control animals that had not been treated. Final colony counts were as follows (mean ± standard deviation): controls, 10.12 ± 1.51 log₁₀ CFU/g of vegetation; evernimicin, 7.22 ± 2.91 log₁₀ CFU/g of vegetation; vancomycin, 5.65 ± 1.76 log₁₀ CFU/g of vegetation. The difference between the evernimicin and vancomycin groups was not significant. These results confirmed the bacteriostatic activity of evernimicin in vivo in an experimental model of severe MRSA infection.