The pandemic HIV infection, the more frequent use of immunosuppressive treatment, and the improved long-term prognosis of immunocompromised patients due to better supporting therapies have resulted in an increase in the prevalence of immunodeficiencies. Highly active antiretroviral therapy (HAART) can improve immunocompetence in HIV patients, even when the immunodeficiency is far advanced. This has resulted in an impressive and lasting lowering of the morbidity and mortality associated with HIV infection. However, immune reconstitution may exacerbate subclinical opportunistic infections or autoimmune diseases, or result in an unexpected, paradoxical aggravation of intercurrent inflammatory diseases. The atypical inflammatory conditions have a number of synonymous names: immune restoration disease (IRD), immune reconstitution syndrome (IRS), or immune reconstitution inflammatory syndrome (IRIS). In the light of specific differential therapeutic consequences, it is important to distinguish the clinical presentation from that of corresponding opportunistic infections. However, diagnostic and therapeutic standards for IRIS have not yet been worked out. The present overview also points to possible diagnostic pitfalls, and makes suggestions for a possible classification of the condition and the therapeutic options.