We analyzed the outcome of 116 patients with prosthetic valve endocarditis treated between 1975 and 1983 and used multivariate analysis to identify risk factors for in-hospital mortality and bad outcome during follow-up. Complicated prosthetic valve endocarditis was defined as the presence of a new or changing heart murmur, new or worsening heart failure, new or progressive cardiac conduction abnormalities, or prolonged fever during therapy. Complicated prosthetic valve endocarditis was present in 64% of patients; factors associated with complicated prosthetic valve endocarditis included aortic valve infection (odds ratio 4.3, p = 0.002) and onset of endocarditis within 12 months of the cardiac operation (odds ratio 5.5, p = 0.0001). The in-hospital mortality rate for prosthetic valve endocarditis was 23%; patients with complicated prosthetic valve endocarditis had a higher mortality than patients with uncomplicated infection (odds ratio 6.4, p = 0.0009). Combined medical-surgical therapy was used in 39% of patients; surgical therapy was more common in patients with complicated prosthetic valve endocarditis (odds ratio 16, p less than 0.0001) and in patients infected with coagulase-negative staphylococci (odds ratio 3.9, p = 0.003). Survival after initially successful therapy for prosthetic valve endocarditis was adversely affected by the presence of moderate or severe congestive heart failure at hospital discharge (p = 0.03). Bad outcome during follow-up (death, relapse of prosthetic valve endocarditis, or subsequent cardiac operation related to sequelae of the original infection) was more common in the medical than the medical-surgical therapy group (p = 0.02). The difference in long-term outcome between patients treated initially with medical or with medical-surgical therapy was particularly evident in those with complicated prosthetic valve endocarditis (p = 0.008). The presence of complicated prosthetic valve endocarditis is a central variable in assessing prognosis and planning therapy; the majority of patients with complicated prosthetic valve endocarditis are best treated with medical-surgical therapy. Those who are not treated surgically during their initial hospitalization are at high risk for progressive prosthesis dysfunction and require careful follow-up.