Naomi F Walker,1–3 James Scriven,2–4 Graeme Meintjes,1–3 Robert J Wilkinson1,2,5 1Department of Medicine, Imperial College London, London, UK; 2Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; 3Department of Medicine, University of Cape Town, Cape Town, South Africa; 4Liverpool School of Tropical Medicine, Liverpool, UK; 5MRC National Institute of Medical Research, London, UK Abstract: Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed. Keywords: antiretroviral therapy, tuberculosis, IRIS, diagnosis, complications