The beneficial effects of therapy combining an antibiotic and dexamethasone have been reported in human studies on meningitis and in experimental studies on septic arthritis, nephritis, and endophthalmitis. Since most patients with staphylococcal endocarditis need a combination of medical and surgical treatment, the purpose of this study was to determine whether the addition of dexamethasone to vancomycin has any beneficial effect regarding the degree of valve tissue damage or the course of experimental aortic valve endocarditis caused by a methicillin-resistant strain of Staphylococcus aureus. Rabbits with catheter-induced aortic valve vegetations were randomly assigned to a control group and to groups receiving dexamethasone (0.5 mg/kg of body weight, intravenously [i.v.], twice a day [b.i.d]), vancomycin (30 mg/kg, i.v., b.i.d), or dexamethasone plus vancomycin, for a total of 10 doses (two doses per day for 5 days). The severity of valve tissue damage was significantly less in groups receiving vancomycin plus dexamethasone compared with that of the group receiving vancomycin alone (P < 0.001). The severity of tissue damage was inversely correlated with the mean polymorphonuclear leukocyte number in valve tissue. No statistically significant differences were observed between the vancomycin-treated group and the vancomycin-plus-dexamethasone-treated group in survival, blood culture sterilization rate, or reduction of the microbial burden (in CFU per gram) in valvular tissue. In conclusion, treatment with a combination of vancomycin and dexamethasone for 5 days reduces the severity of valve tissue damage in experimental staphylococcal aortic valve endocarditis. These findings could have significant implications in the treatment of staphylococcal endocarditis and deserve further confirmation in clinical trials.