Since the introduction of highly active antiretroviral therapy, survival rates for human immunodeficiency virus (HIV) infection have markedly improved, but less of an effect has been found for HIV-associated neurocognitive disorders. On the basis of our previous findings, we hypothesized that increased production of osteopontin might contribute to the persistence of central nervous system (CNS) dysfunctions. We found increased levels of osteopontin in the brains of humans with HIV encephalitis and monkeys with simian immunodeficiency virus (SIV) encephalitis. In cerebrospinal fluid, osteopontin levels were found to be elevated in HIV-infected individuals, regardless of their neuropsychological status. However, plasma osteopontin levels were significantly increased in individuals with HIV-associated dementia. In addition, a longitudinal study of monkeys revealed that plasma levels of osteopontin increased before the development of SIV-induced neurological and clinical abnormalities. Thus, plasma levels of osteopontin are significantly correlated with HIV-induced CNS dysfunction in the current era of efficacious antiviral treatment, and this finding suggests that the development of interventions to modulate osteopontin production or signaling might be beneficial in the prevention or treatment of HIV-induced CNS disorders.