Infection of the skeletal system in immunocompromised hosts is a legitimate concern. Indolent presentations and unusual pathogens are more common among impaired hosts. Delays in diagnosis may lead to joint destruction and disability. Accurate diagnosis requires specific requests for the microbiology laboratory to plate specimens onto fungal, mycobacterial, viral, and mycoplasmal culture medium. Effective treatment appears to require (1) open drainage or debridement of the affected site more frequently in immunocompromised patients than in normal hosts and (2) prolonged antimicrobial therapy.