This study analyzed the profile and outcome of surgically versus medically treated patients with prosthetic valve infective endocarditis (PVE). From 2000 to 2006, 80 patients >16 years of age (median 71) with definite PVE according to modified Duke criteria were included. The medically treated group was separated into deliberately conservative and perforce conservative treatments, the latter group including patients with contraindications to a cardiosurgical intervention. The most frequent causative micro-organisms were staphylococci. Forty-six percent of patients were surgically treated, 34% had deliberately conservative treatment, and 20% had perforce conservative treatment. Six-month mortality was 29%; 27% of surgically treated patients died, 4% deliberately conservatively patients died, and 75% perforce conservatively treated patients died. Septic shock, multiorgan failure, and type of treatment were significantly associated with death in univariable analysis. Multivariable analysis revealed that type of treatment (perforce conservative) and septic shock predicted death in patients with PVE. Survival was most favorable in deliberately conservatively treated patients, including PVE due to Staphylococcus aureus. In conclusion, there remains a role for watchful waiting in patients with PVE without evidence of major complications. Moreover, patients with uncomplicated S. aureus PVE can be treated successfully without cardiac surgery. Conversely, patients with major complicated PVE should preferentially undergo surgery. Predictors of mortality in patients with PVE included septic shock and perforce conservative treatment.