This chapter presents (i) unifying neuropathological criteria for diagnosing HIV encephalopathy to decrease variability in diagnostic terms and criteria, (ii) an overview of the neuropathology of HIV infection, and (iii) data to show that highly active antiretroviral therapy (HAART) can reduce the severity of HIV encephalopathy but does not prevent monocyte trafficking to the brain. To determine the prevalence of HIV encephalopathy in autopsies before and after the introduction of HAART in 1995-1996, a group of physicians in Frankfurt, Germany, reevaluated neuropathology reports of autopsies performed on 436 HIV-infected patients between 1985 and 1999 at the Edinger Institute. Throughout the study period, HIV encephalopathy was the most common histological finding and the only neuro-AIDS complication that increased over time; the prevalence of cytomegalovirus (CMV), toxoplasmosis, cryptococcosis, and central nervous system (CNS) lymphoma decreased. The diagnosis of CMV infection of the brain required the identification of cells with the characteristic cytoplasmic and intranuclear inclusions of CMV. Gross examination of the brain and spinal cord at autopsy may reveal no lesions specific for HIV encephalopathy. Brain atrophy is present in severe cases and can be mild to marked, with hydrocephalus ex vacuo. New neuropsychological impairment was twice as common in the pre-HAART group as in the post-HAART group and occurred sooner in the course of HIV. The treatment of choice for HIV dementia and HIV-associated neurocognitive decline is HAART.