Drug injection often results in soft tissue infections of the upper extremity. The purpose of this study was to determine the distinct bacteriologic features of soft tissue abscesses in injecting drug abusers in order to provide guidelines for optimal empiric antibiotic therapy. Admissions to the musculoskeletal infection ward at our institution from 1993 to 2005 were screened to identify patients with a history of injecting illicit drugs and a diagnosis of a soft tissue abscess. Eight hundred fifty-five patients met these criteria and were included in this retrospective study. There were 638 male and 217 female patients with a mean age of 41.5 years (18 to 75 years). In the 694 patients with positive cultures the most common organism was Staphylococcus aureus, identified in 359 patients (52%). A progressive increase in the prevalence of ORSA was observed; ORSA comprised 5% of Staphylococcus aureus infections in 1999, 50% in 2001, 56% in 2003, and 82% in 2005. Microaerophilic Streptococcus was present in 37% of culture-positive cases and other anaerobes in 10%. Infections were monomicrobial in 366 of 694 patients (53%) and polymicrobial in 328 of 694 patients (47%). Staphylococcus aureus is the most common pathogen in soft tissue abscesses in injecting drug abusers with an increasing proportion of ORSA. In addition to surgical decompression of abscesses, broad-spectrum empiric antibiotic therapy may be necessary.