Fever of unknown or uncertain origin (FUO) constitutes a common clinical challenge in patients infected with HIV. It is usually caused by disseminated opportunistic infection, and the relative frequency of each cause of FUO is influenced by multiple factors including CD4 count, geographic setting, and local prevalences of infectious agents, which may provide clues to the diagnosis. Infections presenting as FUO in the HIV population occur most often in the late stages of the disease and high diagnostic suspicion for mycobacterial disease should be maintained when evaluating these patients, particularly in areas of high prevalence. This article discusses the causes, diagnosis, and treatment of FUO in HIV-infected individuals.