The introduction of combination antiretroviral therapy for HIV infection has prolonged the lives of patients with AIDS. It is increasingly being recognized, however, that following initiation of this therapy some patients can develop a paradoxical neurological deterioration, despite dramatic improvements in HIV viral load and CD4+ T-cell counts. This immune reconstitution inflammatory syndrome (IRIS) in the CNS is emerging as an important neurological complication, particularly as antiretroviral therapy is now becoming readily available worldwide. Currently, there are no guidelines for prevention, diagnosis or treatment of the CNS manifestations of IRIS. Even in patients with an acute presentation, the diagnosis can be challenging. Furthermore, it is possible that more-chronic forms of the syndrome exist but remain unrecognized. Here, we review the various clinical presentations of CNS IRIS, and discuss options for their management.