The study analyzed 1779 patients with definite infective endocarditis (IE) caused by Staphylococcus aureus (S. aureus) across 39 medical centers in 16 countries. S. aureus was the most common pathogen, accounting for 31.4% of cases. Health care-associated S. aureus IE was the most common form, accounting for 39.1% of cases, with significant regional variation. Methicillin-resistant S. aureus (MRSA) IE was more common in the United States and Brazil than in Europe and Australia/New Zealand. Persistent bacteremia was independently associated with MRSA IE. Patients in the United States were more likely to have diabetes, be hemodialysis-dependent, and have persistent bacteremia. S. aureus IE was the leading cause of IE in many regions, with significant regional differences in patient characteristics. The study highlights the increasing role of health care-associated infections and MRSA in IE, emphasizing the need for further research to understand regional variations and improve treatment strategies. The main outcome measure was in-hospital mortality, which was higher in health care-associated S. aureus IE compared to community-acquired cases. The study underscores the importance of infection control measures and the need for new interventions to address the growing burden of S. aureus IE.The study analyzed 1779 patients with definite infective endocarditis (IE) caused by Staphylococcus aureus (S. aureus) across 39 medical centers in 16 countries. S. aureus was the most common pathogen, accounting for 31.4% of cases. Health care-associated S. aureus IE was the most common form, accounting for 39.1% of cases, with significant regional variation. Methicillin-resistant S. aureus (MRSA) IE was more common in the United States and Brazil than in Europe and Australia/New Zealand. Persistent bacteremia was independently associated with MRSA IE. Patients in the United States were more likely to have diabetes, be hemodialysis-dependent, and have persistent bacteremia. S. aureus IE was the leading cause of IE in many regions, with significant regional differences in patient characteristics. The study highlights the increasing role of health care-associated infections and MRSA in IE, emphasizing the need for further research to understand regional variations and improve treatment strategies. The main outcome measure was in-hospital mortality, which was higher in health care-associated S. aureus IE compared to community-acquired cases. The study underscores the importance of infection control measures and the need for new interventions to address the growing burden of S. aureus IE.