Immune reconstitution inflammatory syndrome (IRIS) is an increasingly recognized phenomenon of paradoxical worsening of patients with acquired immunodeficiency syndrome (AIDS) upon initiation of highly active antiretroviral therapy (HAART). To date, there have been limited reports of IRIS in the central nervous system (CNS). Here, the authors describe a 43-year-old man with AIDS who presented with subacute meningitis. No pathogenic organism was identified by routine diagnostic tests, and he was treated empirically with an antituberculous regimen and initiated on HAART therapy. Soon after, he had a precipitous neurologic decline leading to his death. Postmortem evaluation showed a basilar Candida meningitis as well as vasculitis characterized by CD8+ T-cell infiltration, consistent with IRIS. The authors discuss the challenges in diagnosing fungal meningitides and the risks of initiating HAART therapy in those with possible undiagnosed underlying opportunistic infections. Additionally, the authors review the literature regarding CNS IRIS.