Pyomyositis is an acute bacterial infection of skeletal muscle not arising from contiguous infection. It is often hematogenous in origin and typically associated with abscess formation. Our objective was to determine if there were any differences in the clinical presentation of disease between Staphylococcus aureus (SA) and non-Staphylococcus aureus pyomyositis. We also sought to determine if methicillin-resistant SA (MRSA) occurred more frequently during the final years of the study period.A retrospective chart review study at three institutions in two cities.Sixty cases of pyomyositis were identified between 1990 and 2010. Twenty-nine patients were infected with SA while 31 had other bacterial etiologies or were culture negative. Those with a traumatic event prior to the onset of infection were more likely to have a SA infection while SA infected patients were younger. Our first documented case of MRSA occurred in 2005, but the frequency of MRSA infection remained static over the following five years.Pyomyositis is an emerging infection that is underappreciated by many physicians. While MRSA has emerged as the foremost cause of SA infections in a majority of clinical conditions, in this series most patients still had methicillin-sensitive SA as their cause of pyomyositis. In light of the severity of pyomyositis and the potential for bacteremia (either as a source or complication of the infection), empiric SA therapy should be initiated in all patients until the culture results are available.