Reactive hemophagocytic lymphohistiocytosis (HLH) is a disorder reported secondary to infectious, rheumatologic, neoplastic, and immunologic causes. Whereas increasingly recognized in patients infected with HIV, its diagnosis can be problematic in immunocompromised patients recently started on highly active antiretroviral therapy (HAART), undergoing immune reconstitution and encountering opportunistic infections. A young man recently diagnosed as human immunodeficiency virus (HIV) and started on HAART 3 weeks earlier presented with dyspnea and spiking fevers. Evaluation revealed HLH, disseminated Mycobacterium avium complex (MAC) and Histoplasma capsulatum. Prompt treatment of the precipitating conditions led to a reversal of his symptoms and a positive outcome. This is the first reported HLH case in a patient infected with HIV associated with M avium. The juxtaposition of HIV infection itself, reconstitution of the immune system with HAART, opportunistic infections, and HLH may create a confusing presentation with an inflammatory milieu whose pathophysiology is not well understood. Yet, HLH can be highly lethal if not promptly recognized and properly treated.