The prevalence of AIDS-related Kaposi sarcoma (KS) has markedly declined in the era of highly active antiretroviral therapy (HAART) although it remains one of the most common AIDS-defining malignancies. Although immune reconstitution inflammatory syndrome (IRIS)-related KS (IRIS-KS) represents only a fraction of the IRIS cases, it can be a life-threatening situation. This report describes a fatal case of IRIS-KS. A 32-year-old man with HIV/AIDS was initiated on HAART and experienced rapid immunological and virological response to therapy. He subsequently experienced progressively severe dyspnea and papulonodular skin lesions and was admitted to the hospital with hypoxic respiratory failure. Bronchoscopy revealed numerous friable endobronchial lesions. Histopathology of a skin lesion was consistent with KS. The relatively rapid progression of disease in the setting of improvement in immune function after initiating HAART suggested IRIS-KS. This report reviews previously published cases of IRIS-KS and describes risk factors, immunopathogenesis and treatment options. © 2012 Lippincott Williams &Wilkins.