The ability of highly active antiretroviral therapy (HAART) to prevent the onset of HIV‐associated dementia and to prevent or reduce the neuropathological features of HIV encephalitis (HIVE) remains unclear. Using a severe combined immunodeficient (SCID) mouse model of HIVE, we determined the effects of regular HAART treatment on HIVE. Before studying HAART in infected SCID mice, nonmanipulated SCID mice were treated with a single injection of the HAART cocktail (consisting of zidovudine, lamivudine, and indinavir) to determine optimum dosage and sampling time and to measure antiretroviral levels in the brain. After these preliminary studies, SCID mice that were inoculated with either HIV‐infected or uninfected human monocytes were given intraperitoneal (IP) injections of HAART three times daily over a 1‐ and 2‐week period. All three drugs were detected in the brain using a novel drug extraction technique and a modified high‐performance liquid chromatography method. HAART significantly decreased the amount of astrogliosis and viral load in treated mice compared with mice that received vehicle injections. These studies offer insight into the ability of HAART to treat HIV infection of the brain. Ann Neurol 2005