Staphylococcus aureus prosthetic valve endocarditis (SAPIE) is a serious disease. Our objective was to study the clinical, echocardiographic and prognostic characteristics of left-sided SAPIE, and to compare these characteristics with those of left-sided non-S.aureus prosthetic infective endocarditis (NSAPIE) (i.e. left-sided prosthetic infective endocarditis caused by another germ). This was a retrospective analysis of 35 cases of SAPIE among 247 cases of left-sided prosthetic valve endocarditis hospitalized at two university hospitals (Amiens and Marseille, France). SAPIE accounted for 14.1% of the cases of left-sided prosthetic valve endocarditis. SAPIE complications included heart failure (in 42.8% of cases), acute renal failure (in 51.4%), sepsis (in 51.4%), neurological events (in 31.4%), systemic embolic event (in 34.2%) and abscess (in 60.0%). In-hospital mortality occurred in 48.5% of SAPIE cases compared with 16% of NSAPIE cases. A comparison of the SAPIE and NSAPIE groups showed a significant difference in terms of 4-year survival (31.8±7.3% vs 60.1±4.1%; P=0.001). Severe sepsis was the only prognostic factor associated with in-hospital mortality (odds ratio 5.7; P=0.03) and long-term mortality (odds ratio 3.7; P=0.01) in cases of SAPIE. Sepsis-induced multiple organ dysfunction syndrome was the main cause of in-hospital mortality (70.5%). SAPIE is a very serious disease, with elevated in-hospital mortality resulting from sepsis-induced multiple organ dysfunction syndrome. Emergency surgery is recommended in these cases, when possible, before the occurrence of complications, especially severe sepsis.