Infection of the hepatobiliary system is most commonly due to enteric bacteria. We report three unusual cases of acute cholecystitis in which Staphylococcus aureus was the primary pathogen. Infection of the gallbladder with this organism has been rarely described and may be associated with gallstones and obstructive disease as well as acalculous cholecystitis in the setting of staphylococcal bacteremia and endocarditis. Two of our patients had multiple chronic medical conditions and were infected with oxacillin-resistant S. aureus (ORSA) suggesting nosocomial acquisition. Including our cases with a review of the literature, three of nine reports of S. aureus cholecystitis were associated with infectious endocarditis. Thus, the finding of S. aureus cholecystitis with bacteremia is rare and should prompt an investigation for a possible endovascular focus of infection.