Inflammatory mediators play a crucial role in the pathophysiology of several neurodegenerative diseases including acquired immune deficiency syndrome dementia complex. In the present study we identified a link between CXCL10 overexpression in the brain and human immunodeficiency virus dementia and demonstrated the presence of the chemokine CXCL10 and its receptor, CXCR3, in the neurons in the brains of macaques with simian human immunodeficiency virus encephalitis. Using human fetal brain cultures, we showed that treatment of these cells with either SHIV89.6P or viral gp120 resulted in induction of CXCL10 in neurons. Cultured neurons treated with the chemokine developed increased membrane permeability followed by apoptosis via activation of caspase-3. We confirmed the relevance of these findings in sections of human and macaque brains with encephalopathy demonstrating that neurons expressing CXCL10 also expressed caspase-3.