HIV-infected patients are vulnerable to developing altered mental status (AMS) for myriad reasons, including the effects of HIV itself, the accompanying immune dysfunction, associated systemic illness, comorbid psychiatric disorders, and complicated medication regimens. Combination antiretroviral therapy (ART) has decreased the incidence of central nervous system (CNS) opportunistic infections (OIs) and HIV-associated dementia, but the benefits are not absolute. In addition to CNS OIs and complications of complex multisystem disease, immune reconstitution events developing in the early weeks and months after initiating ART may affect the brain and cause AMS. This article examines the epidemiology, diagnosis, and currently available treatment for patients with HIV-related AMS.