The introduction of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection has transformed this disease from a fatal infection to a chronic yet manageable condition by restoring immune function. All the same, this restoration of immune response in some may be associated with deterioration in clinical status, which has been termed immune reconstitution inflammatory syndrome (IRIS). This syndrome often occurs in the context of an underlying opportunistic infection and develops after an interval of weeks to months after the initiation of HAART. Occasionally, IRIS may occur in the brain without any opportunistic infection, which presents as a T cell–mediated encephalitis. This paradoxical infiltration of previously immune suppressed patients with T cells represents a diagnostic challenge and a treatment dilemma. Nonetheless, CNS-IRIS with or without an opportunistic infection can range in severity. Severe cases can be fatal and hence require intervention with steroid treatment. This review discusses the diagnosis, clinical manifestations, risk factors, pathophysiology, and potential treatment strategies of the various forms of IRIS that involve the nervous system.