Immune reconstitution occurs after initiation of highly active antiretroviral therapy in immunodeficient HIV-positive individuals. Unexpected deterioration of inflammatory disease and atypical clinical features resembling symptoms of autoimmune disease may arise. These atypical inflammatory disorders, synonymously summarized as immune reconstitution syndrome, immune restoration disease, and immune restoration inflammatory syndrome (IRIS), are caused by augmentation of inflammation during immune reconstitution in an immunocompromised host. These disorders have to be distinguished from intercurrent infection and rheumatic disease, respectively. Treatment of IRIS consists of elements for both potential differential diagnoses (ie, anti-inflammatory and immunosuppressive drugs, such as in autoimmune disorders and antimicrobial chemotherapy, to decrease the burden of pathogen, such as in infectious disease). Therefore, awareness for IRIS is of increasing importance from a clinical point of view. However, diagnostic criteria and standards of treatment are still preliminary.