Advances in highly active antiretroviral therapy (HAART) have reduced the mortality and improved the quality of life of people living with HIV (PLHIV), as well as changed their spectrum of musculoskeletal problems. Infectious complications in the appendicular skeleton, although declining, are devastating, as they can be fatal or cause serious structural damage and long-term disability. PLHIV are at risk of noninfectious musculoskeletal problems that may be related to HIV infection or treatment, such as inflammatory joint diseases, avascular necrosis, myopathies, and cancers mimicking infection. This chapter reviews the spectrum of musculoskeletal diseases of PLHIV pre- and post-HAART era, emphasizing infectious disease in the appendicular skeleton. The spectrum of causative organisms and their clinical manifestations are discussed, with presentation of representative cases and the usefulness of imaging studies in making the diagnosis.