Highly active antiretroviral treatment (HAART), which has been available for most AIDS patients in France since 1996, has resulted in a dramatic improvement of the progression of the disease. From the survey of our series of 343 brains with acquired immunodeficiency syndrome (AIDS) from patients who died between 1985 and 2002, we found both quantitative and qualitative changes in the pattern of human immunodeficiency virus (HIV) neuropathology. Quantitatively, despite a dramatic decrease in the number of autopsies, brain involvement remained a major cause of death. There was an overall decrease in incidence of cerebral toxoplasmosis, cytomegalovirus encephalitis (CMVE), and HIV encephalitis (HIVE), for which successful treatment is available. This contrasted with the unchanged incidence of progressive multifocal leukoencephalopathy (PML) and malignant non-Hodgkin lymphomas (MNHL). However, when looking closer at the 3 last years, the incidence of diseases affecting patients with severe immunodepression (CMVE, PML, and MNHL) decreased between 2000 and 2002, whereas infections occurring in patients with milder immunodeficiency, toxoplasmosis, varicella-zoster encephalitis (VZVE), or herpes simplex virus encephalitis (HSVE) became more frequent. In addition, we found uncommon types of brain infection such as BK virus encephalitis or general paresis. Finally, we described new variants of HIVE: severe leukoencephalopathy with intense perivascular macrophage and lymphocyte infiltration, possibly due to an exaggerated response from a newly reconstituted immune system, and chronic "burnt out" forms of HIVE as VZVE, toxoplasmosis, or PML, possibly associated with prolonged survival, in which neither inflammation nor organisms could be detected. These findings are compared with those reported in other neuropathological studies from different developed countries.