OBJECTIVE To highlight the importance of immune reconstitution inflammatory syndrome affecting the brain in HIV-infected individuals in the absence of opportunistic infections. To describe the varied clinical manifestations, unifying pathophysiological features and discuss the principles of management of this syndrome. RESULTS Immune reconstitution inflammatory syndrome within the brain is commonly seen in patients with HIV infection upon initiation of antiretroviral drugs. The fulminant forms occur in the face of opportunistic infections or uncontrolled viral replication within the brain. In this case, the enhanced immune response is targeted against the microbial agent, and the brain suffers bystander damage. Treatment requires the combination of the antimicrobial agent, continued antiretrovirals and in some cases corticosteroids. It is increasingly being recognized that despite adequate control of viral replication in the brain, some patients develop a chronic form of T cell encephalitis which appears to be driven by continued production of HIV-Tat protein. In others, the immune response may be targeted against the host antigens in the brain. CONCLUSIONS In patients with central nervous system-immune reconstitution inflammatory syndrome, the use of corticosteroids and strategies that prevent T cell migration into the brain may be needed. Extreme caution is necessary if viral eradication strategies are to be employed that involve activation of viral reservoirs, as these patients may be at risk for developing central nervous system-immune reconstitution inflammatory syndrome.