BACKGROUND The literature contains variable reports on the causative organisms of osteomyelitis and septic arthritis in patients with injecting drug abuse and on the rate of oxacillin-resistant S aureus. It is important to have a clear notion of the organisms to initiate empiric antimicrobial therapy. OBJECTIVE We therefore determined the spectrum of organisms in bone and joint infections in patients who were injecting drug users. METHODS We retrospectively reviewed the medical records of 215 patients (154 male, 61 female) with a history of injecting drug abuse and concurrent bone and/or joint infection from 1998 to 2005. The mean age was 43 years (range, 23-83 years). Osteomyelitis was present in 127 of the 215 patients (59%), septic arthritis in 53 (25%), and both in 35 (16%). The lower extremity was most commonly involved (141 cases, 66%), with osteomyelitis of the tibia present in 70 patients (33%) and septic knee arthritis in 30 patients (14%). RESULTS Cultures yielded predominately Gram-positive bacteria: Staphylococcus aureus in 52% and coagulase-negative Staphylococcus in 20%. The proportion of oxacillin-resistant S aureus among S aureus infections increased from 21% in 1998 to 73% in 2005. Gram-negative organisms were present in 19% of infections and anaerobes in 13%. Patients with osteomyelitis had a higher prevalence of polymicrobial infections (46% versus 15%), infections due to Gram-negative organisms (24% versus 9%), and anaerobic infections (19% versus 6%) compared to patients with septic arthritis. CONCLUSIONS These findings suggest broad-spectrum empiric antibiotic therapy, including vancomycin, should be considered for bone and joint infections in patients with injecting drug abuse. METHODS Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.