Immune reconstitution inflammatory syndrome (IRIS) after HAART may become manifest in form of aseptic severe leucoencephalopathy. All HIV-1-positive patients in this case series had widespread laboratory tests and follow-up MRI in order to investigate the course and the underlying pathophysiology of IRIS-associated leucoencephalopathy. All patients were treated with corticosteroids, in spite of additional immunosuppression. Three patients were successfully treated with corticosteroids and survived up to now, one died. A neuropathological examination was performed showing massive aseptic intraparenchymal and perivascular invasion of cytotoxic CD8+ cells. It is assumed that IRIS-associated leucoencephalopathy is based on other preconditions in Africans and Caucasians.