Staphylococcus aureus is the leading cause of infectious endocarditis and its mortality has remained high despite better diagnostic and therapeutic procedures over time. We conducted a retrospective review of 133 cases of definite S. aureus endocarditis seen at a single tertiary care hospital over 22 years to assess changes in the epidemiology and incidence of the infection, manifestations, outcome, risk factors for mortality, and impact of cardiac surgery on prognosis.Patients were classified into 2 groups: 1) right-sided endocarditis (64 patients) and 2) left-sided endocarditis (69 patients). While the number of cases of left-sided endocarditis remained steady at 1-3 cases per 10,000 admissions, the incidence of right-sided endocarditis, after a peak in the early 1990s, declined to almost disappear in 2001. Among the cases of right-sided endocarditis, we found 2 subsets of patients with different clinical features and prognosis: the first subset comprised 53 intravenous drug abusers, and the second subset comprised 11 patients with catheter-associated S. aureus bacteremia and endocarditis. Fifty-one patients were human immunodeficiency virus (HIV)-positive drug abusers, most of whom (80.3%) had right-sided endocarditis. We did not find differences in mortality between HIV-positive and HIV-negative individuals; mortality seemed to depend more on the site of the heart involved than on HIV status.Among the cases of left-sided endocarditis, the mitral valve was more commonly involved than the aortic valve (61% vs. 30%). Overall, 74% of patients with left-sided endocarditis developed 1 or more cardiac or extracardiac complication. In comparison, only 23.4% of patients with right-sided endocarditis developed complications.Prosthetic valve endocarditis (PVE) was hospital-acquired more frequently than native valve endocarditis (NVE). Patients with PVE had a shorter duration of symptoms until diagnosis and presented with or developed cardiac murmurs less frequently than patients with NVE. Cardiac failure (49%), renal failure (43%) and central nervous system (CNS) events (35%) were frequently observed in patients with both PVE and NVE. Valve replacement was more frequently needed and more rapidly performed in patients with PVE than in their counterparts with NVE.The overall mortality of patients with right-sided endocarditis was 17%. While the mortality of right-sided endocarditis in injection drug users was 3.7%, the mortality of patients with right-sided endocarditis associated with infected intravenous catheters was 82% (odds ratio [OR], 0.01; 95% confidence interval [CI], 0.001-0.07). For left-sided endocarditis mortality was 38% and was not significantly different in patients with NVE or PVE (OR, 0.65; 95% CI, 0.23-1.87). CNS complications were associated with mortality in both NVE (OR, 6.55; 95% CI, 1.78-24.04) and PVE (OR, 32; 95% CI, 2.63-465.40). Development of 2 or 3 complications was associated with an increased risk of mortality (OR, 5.59; 95% CI, 1.08-28.80 and OR, 9.25; 95% CI, 1.36-62.72 for 2 vs. 1 complication and for 3 vs. 2 complications, respectively).Surgical treatment did not significantly influence mortality in cases of NVE, (OR, 3.19; 95% CI, 0.76-13.38) but significantly improved the prognosis of patients with PVE (OR, 69; 95% CI, 2.89-1647.18).S. aureus endocarditis is an aggressive, often fatal, infection. The results of the current study suggest that valve replacement will improve the outcome of infection, particularly in patients with PVE.