Highly active antiretroviral therapy (HAART) can improve immune system function through suppression of HIV-1 replication. In some cases, a vigorous paradoxical immune response may develop. Individuals treated effectively can, because of low immune reactivity, suffer from diseases which run subclinically until HAART is introduced. These symptoms are termed IRS (immune reconstitution syndrome/immune recovery syndrome), IRD (immune restoration disease), and IRIS (immune restoration inflammatory syndrome). There are some predisposing factors, such as long-lasting HIV-1 infection, severe immunodeficiency, rapid immune restoration, immune dysregulation during immune reconstitution, subclinical infection, and genetic susceptibility. A common feature of IRS is clinical symptoms different from those observed usually in HIV-1-infected patients. Sarcoidosis and some autoimmune diseases are less common. They are present for the first time or as an exacerbation of established diseases. Diagnosis is difficult. It is very often impossible to identify the pathogen. The clinical symptoms in patients receiving HAART should be differentiated into IRS, ineffective HAART leading to the development of opportunistic infection, and drug toxicity.