In HIV-infected individuals, paradoxical reactions after the initiation of antiretroviral therapy (ART) are associated with a variety of underlying infections and have been called the immune reconstitution inflammatory syndrome (IRIS). In cases of IRIS associated with tuberculosis (TB), two distinct patterns of disease are recognized: (i) the progression of subclinical TB to clinical disease after the initiation of ART, referred to as unmasking, and (ii) the progression or appearance of new clinical and/or radiographic disease in patients with previously recognized TB after the initiation of ART, the classic or "paradoxical" TB-IRIS. IRIS can potentially occur in all granulomatous diseases, not just infectious ones. All granulomatous diseases are thought to result from interplay of inflammatory cells and mediators. One of the inflammatory cells thought to be integral to the development of the granuloma is the CD4 T lymphocyte. Therefore, HIV-infected patients with noninfectious granulomatous diseases such as sarcoidosis may also develop IRIS reactions. Here, we describe IRIS in HIV-infected patients with TB and sarcoidosis and review the basic clinical and immunological aspects of these phenomena.