Research since the early 1970s has generated significant support for the concept that clinical manifestations of infectious diseases are often due more to the host immune response rather than to direct effects of a particular microbe. Perhaps the longest recognized example of the dominance of an immune response in determining a clinical presentation occurs in Mycobacterium leprae infection. However, the introduction of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) infection has markedly increased the appreciation for the dramatic interaction that can occur between microbes and a recovering immune system. The immune restoration mediated by HAART has markedly decreased the rates of opportunistic infections among HIV-infected patients, leading to dramatically lower mortality rates. However, in some patients, the recovery of immune function can lead to an inflammatory reaction aimed at either previously recognized or subclinical microbes or even autoimmune disorders. Multiple names have been given to this syndrome, including immune recovery disease, immune restoration disease, and immunoreconstitution disease. For the purposes of this chapter, we will utilize the term immune reconstitution inflammatory syndrome (IRIS) as it includes one of the defining features of these patients' presentations, i.e., inflammation.