A significant proportion of patients present with the immune reconstitution inflammatory syndrome (IRIS) after commencing antiretroviral therapy (ART). This syndrome is most frequently associated with infective causes. The lack of evidence-based treatment guidelines poses challenges in the management of these patients. Alternative causes for deterioration should be excluded, and optimization of treatment for the underlying opportunistic infection is essential. In addition, anti-inflammatory or immunomodulatory therapy may be considered, particularly in severe cases. Corticosteroids, the only treatment for which clinical trial data exist (for treating paradoxical tuberculosis-associated IRIS), are the treatment most frequently used in IRIS. Limited anecdotal reports of benefit exist for other agents, including NSAIDs, pentoxifylline, montelukast, thalidomide, and hydroxychloroquine. Therapeutic procedures (eg, aspiration of pus collections) play an important role in some patients. Interruption of ART may be considered in life-threatening forms of IRIS.