The study documents the global emergence of healthcare-associated *Staphylococcus aureus* (S aureus) endocarditis (IE) and methicillin-resistant *S aureus* (MRSA) IE, and evaluates regional variations in patients with S aureus IE. The International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) enrolled 1779 patients with definite IE from 39 medical centers in 16 countries between June 2000 and December 2003. *S aureus* was the most common pathogen, accounting for 31.4% of cases. Healthcare-associated IE was the most common form of S aureus IE, with 218 patients (39.1%) infected. Patients with healthcare-associated IE were more likely to be from the United States, older, and more likely to be infected with MRSA. In-hospital mortality was higher in patients with healthcare-associated IE, and persistent bacteremia was independently associated with MRSA IE. The findings highlight the increasing importance of healthcare-associated IE and the need for improved infection control measures.The study documents the global emergence of healthcare-associated *Staphylococcus aureus* (S aureus) endocarditis (IE) and methicillin-resistant *S aureus* (MRSA) IE, and evaluates regional variations in patients with S aureus IE. The International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) enrolled 1779 patients with definite IE from 39 medical centers in 16 countries between June 2000 and December 2003. *S aureus* was the most common pathogen, accounting for 31.4% of cases. Healthcare-associated IE was the most common form of S aureus IE, with 218 patients (39.1%) infected. Patients with healthcare-associated IE were more likely to be from the United States, older, and more likely to be infected with MRSA. In-hospital mortality was higher in patients with healthcare-associated IE, and persistent bacteremia was independently associated with MRSA IE. The findings highlight the increasing importance of healthcare-associated IE and the need for improved infection control measures.