Our objective was to determine if highly active antiretroviral therapy (HAART), previously shown to ameliorate several pathological features of HIV encephalitis (HIVE) in a SCID mouse model, would also reduce additional established pathological features of HIV: cognitive dysfunction, TNF-α, production, and reduced MAP-2 expression. SCID mice with HIVE and control mice inoculated with uninfected monocytes were administered HAART or saline. The HIV pathological features evaluated included astrogliosis, viral load, neuronal apoptosis, MAP-2 expression, mouse TNF-α mRNA production and learning acquisition and retention. HAART reduced the HIV-induced viral load, and the astro- and microgliosis as previously observed; this effect was extended to HIV-induced increases in TNF-α mRNA production. In contrast, although HIV produced the cognitive deficits previously observed and also decreased MAP-2 expression in the area surrounding the injected HIV-infected human monocytes, HAART did not attenuate these effects. Interestingly, there was no neuronal apoptosis evident at the time point reflecting the above pathology. The results of this study combined with previous reports indicate that HAART reduces TNF-α mRNA, viral load and astrogliosis; however, HAART does not improve HIV-induced cognitive dysfunction or MAP-2 decreases. These results suggest that viral load, astrogliosis, TNF- α and apoptosis are not prominent in the pathogenesis of early functional deficits related to decreased MAP-2 expression or cognitive dysfunction in HIVE in SCID mice.