A subset of HIV-infected individuals who receive antiretroviral therapy (ART) develop a paradoxical pathological response that significantly increases morbidity and sometimes mortality. Following the induction of highly active ART, a rapid decline in the viral load results within weeks and coincides with a steep rise in the CD4(+) T-cell counts and immune hyperactivation. Although no mechanistic pathway has been elucidated for the development of immune reconstitution inflammatory syndrome (IRIS), it is thought that change in the nature of the immune response is a predominant factor in the development of reconstitution disease. In this article, we review the current state of knowledge in this field and provide a model for the development of IRIS.