The mortality rate associated with Staphylococcus aureus prosthetic valve endocarditis (PVE) remains high. To identify clinical events associated with an increased risk of death among patients with S. aureus PVE and to evaluate the role of valve replacement surgery in reducing mortality, we conducted a retrospective cohort study of patients who met strict criteria for definite S. aureus PVE. The primary endpoint for the study was survival at 3 months from the date of diagnosis. S. aureus PVE was diagnosed in 33 patients. Of these, 14 (42%) died within 90 days of the diagnosis. Cardiac complications were detected in 22 (67%), and central nervous system (CNS) complications were detected in 11 (33%). A stepwise logistic regression multivariate model demonstrated that cardiac complications, but not CNS complications, were associated with increased mortality and that performing valve replacement surgery during antibiotic therapy was associated with decreased mortality. These associations were confirmed by using a Cox proportional hazards model with time-dependent covariates to control for survival bias. Performing valve replacement surgery during antimicrobial therapy will reduce the mortality among patients with S. aureus PVE, even those without evidence of cardiac complications.