Individuals with human immunodeficiency virus infection who commence antiretroviral therapy when they are very immunodeficient are susceptible to immune reconstitution disorders. The most common disorders are the various forms of immune restoration disease (IRD) that appear to result from the restoration of a dysregulated immune response against pathogen-specific antigens. Essentially, any pathogen that can cause an opportunistic infection as a result of cellular immunodeficiency can provoke IRD when pathogen-specific immune responses recover during antiretroviral therapy. In resource-poor countries, Mycobacterium tuberculosis and Cryptococcus neoformans are the most significant pathogens, because the former causes substantial morbidity and the latter causes substantial mortality. IRD associated with these pathogens is characterized by severe inflammatory responses and is often referred to as immune reconstitution inflammatory syndrome. Prevention and treatment strategies for IRD are being developed, but preliminary data have demonstrated the efficacy of corticosteroid therapy in severe cases. Immune reconstitution after antiretroviral therapy may also be associated with autoimmune disease or sarcoidosis, both of which appear to have an immunopathogenesis that is different from that of IRD.