Immune reconstitution inflammatory syndrome (IRIS) is a potentially life-threatening phenomenon associated with the initiation of antiretroviral therapy in patients with acquired immunodeficiency syndrome due to a human immunodeficiency virus (HIV) infection. It is thought to be an exaggerated inflammatory response to an existing pathogen or even its antigen. We present a case of IRIS due to a non-tuberculous mycobacteria infection in a young patient with HIV infection who was recently started on therapy. This case highlights the challenges of making such a diagnosis and the importance of multidisciplinary team discussions with pulmonary and infectious diseases for optimal management of these patients.