Patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) are susceptible to a variety of complications that can affect the musculoskeletal system. These complications can be infectious, inflammatory, or neoplastic or can take some other form. Infection (cellulitis, necrotizing fasciitis, soft-tissue abscess, pyomyositis, osteomyelitis, septic arthritis) is the most common complication. Inflammatory processes include various arthritides as well as polymyositis. Non-Hodgkin lymphoma and Kaposi sarcoma are the two most common neoplasms in this patient population. Miscellaneous disorders include osteonecrosis, osteoporosis, rhabdomyolysis, anemia-related abnormal bone marrow, and hypertrophic osteoarthropathy. The underlying mechanisms leading to these diseases are complex and not fully understood but are thought to be multifactorial. Radiology may play an important role in early diagnosis and treatment planning in this population, in whom clinical and laboratory findings are commonly equivocal and nonspecific. Although biopsy is often necessary for the final diagnosis, it is important for the radiologist to be familiar with the different types of musculoskeletal disease in HIV-positive and AIDS patients so that an appropriate differential diagnosis can be established.