A high proportion of individuals with HIV infection currently are diagnosed at an advanced stage of disease (late presenters), increasing their risk for immune reconstitution inflammatory syndrome (IRIS). IRIS typically occurs within 6 months of initiation of antiretroviral therapy (ART) in patients with low CD4+ cell counts and can occur before any marked elevation in CD4+ count is achieved on ART. In addition to low CD4+ count at ART initiation, 2 other major clinical predictors of IRIS are preexisting opportunistic infection (including subclinical infection) and shorter treatment period for opportunistic infection prior to starting ART. Mycobacterial infection-associated IRIS, including tuberculosis (TB)-associated IRIS, and cryptococcal infection-associated IRIS are the most common forms of the syndrome. Corticosteroid prophylaxis and early treatment can be effective in reducing incidence of TB-IRIS and severity of symptoms in select patients. Sterilization of the cerebrospinal fluid should be achieved prior to starting ART in patients with TB meningitis and cryptococcal meningitis. This article summarizes a presentation by Irini Sereti, MD, MHS, at the International Antiviral Society-USA (IAS-USA) continuing education program held in Washington, DC, in April 2019.