The use of highly active antiretroviral therapy (HAART) has led to a substantial decrease in the frequency of opportunistic infections among HIV-infected individuals, along with a significant reduction in their mortality rate. However, a subgroup of HAART-treated patients will exhibit paradoxical deterioration in their clinical status, despite satisfactory control of viral replication and improvements in CD4 lymphocyte counts. This clinical deterioration, known as the immune restoration syndrome or immune reconstitution inflammatory syndrome (IRIS), is a result of an exuberant inflammatory response towards previously diagnosed or incubating opportunistic pathogens, as well as responses towards other as yet undefined antigens. A variety of manifestations of IRIS have been described, most prominently including Mycobacterium avium complex lymphadenitis, paradoxical exacerbations of pulmonary and CNS Mycobacterium tuberculosis infection, paradoxical exacerbations of Cryptococcus neoformans meningitis and cytomegalovirus uveitis. Treatment for this disorder includes continuation of primary therapy against the offending pathogen in order to decrease the antigenic load, continuation of effective HAART, and judicious use of anti-inflammatory agents. Although the clinical manifestations of IRIS are sometimes dramatic, and result in substantial morbidity, the fact that these patients are capable of generating an inflammatory response allows many of them to ultimately discontinue secondary prophylaxis for the offending pathogen.