Nontuberculous mycobacterial infections are well known to occur in patients with human immunodeficiency virus infection. However, spondylitis due to mycobacteria other than Mycobacterium tuberculosis is uncommon. We report a case of biopsy- and culture-proven Mycobacterium xenopi spondylitis in an AIDS patient and discuss approaches to diagnosis and therapy. This case serves to highlight the potential pathogenic role of this usually environmental commensal organism in severely immunosuppressed AIDS patients and uncertainties in their management, given the scarce data on appropriate therapy for this organism.