The role of brain HIV load in the pathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. To try and determine if the amount of HIV drives the severity of pathology, a severe combined immunodeficient (SCID) mouse model of HIV encephalitis (HIVE) was utilized to determine the effectiveness of a systemically administered combined antiretroviral (cART) regimen. SCID mice were inoculated intracerebrally with HIV-infected or uninfected (control) human macrophages and treated subcutaneously with cART or saline for 10 days. Immunohistochemistry was then used to examine gliosis and neuronal damage. Drug levels were measured in brain and plasma using high-performance liquid chromatography. Peak plasma and brain levels of atazanavir, tenofovir, and emtricitabine were determined to be 1 h post-injection of cART therapy. cART significantly reduced neuropathological features of HIVE, including astrogliosis and the presence of mononuclear phagocytes, and ameliorated reduced MAP2 (neuronal integrity) staining. However, cART did not eradicate HIV from the brain. Using this animal model of HIVE, these data indicate effective penetration of cART reduces brain viral loads and HIV pathology, possibly by eliminating the production of HIV proteins, virus infected cells, or both. Importantly, these data suggest that viral load directly affects the extent of pathology seen in the brain, particularly neuronal damage, which implies that more effective suppression of HIV in the CNS could reduce currently highly prevalent forms of HAND. However, these data also strongly suggest that cART will not eliminate HIV from the brain and that adjunctive therapies must be developed.