Seventy-five episodes of prosthetic valve endocarditis from Staphylococcus epidermidis were studied retrospectively. Methicillin-resistant isolates caused 53 (87%) of 61 infections occurring within 1 year of surgery but only two of the nine after 1 year (p < 0.001). Resistance to methicillin was heterogeneic and extended to the cephalosporins. Of 55 isolates, 43 (78%) were susceptible to gentamicin and all to vancomycin and rifampin. In 55 patients, prosthetic valve endocarditis was complicated by tissue invasion or valve dysfunction. Among these 55 patients, 30 of the 32 who were cured needed surgery. Prosthetic valve endocarditis from methicillin-resistant S. epidermidis was cured in 21 of 26 patients treated with vancomycin and 10 of 20 treated with beta-lactam antibiotic therapy (p = 0.055). Cure rates of patients treated with vancomycin but not beta-lactam antibiotics were increased by the addition of rifampin or gentamicin to therapy. Prosthetic valve endocarditis from methicillin-resistant S. epidermidis should be treated with vancomycin plus rifampin, or an aminoglycoside. Surgical intervention is important in treating complications of prosthetic valve endocarditis.