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To investigate the role of the uPA\/uPAR system in the pathophysiology of acquired immunodeficiency syndrome dementia complex (ADC), we measured soluble uPAR (suPAR) levels in cerebrospinal fluid (CSF) and plasma from human immunodeficiency virus (HIV)\u20101\u2013infected patients and controls. CSF suPAR levels were significantly higher in HIV\u20101\u2013infected patients than in controls and in patients with ADC or opportunistic CNS infections (CNS\u2010OIs) than in neurologically asymptomatic patients, irrespective of HIV\u20101 disease stage. The highest levels of suPAR were found in patients with ADC, and among those with CNS\u2010OIs in patients with cytomegalovirus encephalitis or cryptococcosis. Plasma suPAR levels were higher in HIV\u20101\u2013infected patients than in controls and increased with HIV\u20101 disease stage regardless of the presence of CNS disease. In patients with ADC or CNS\u2010OIs, CSF suPAR levels correlated with CSF HIV\u20101 RNA, but not with plasma suPAR concentrations. Highly active antiretroviral therapy was associated with a significant and parallel decrease of both CSF suPAR and HIV\u20101 RNA. In brain tissue from patients with HIV\u20101 encephalitis, uPAR was highly expressed by microglial and multinucleated giant cells staining positively for HIV\u20101. The overexpression of uPAR in the CNS of patients with ADC suggests that the uPA\/uPAR system may contribute to the tissue injury and neuronal damage in this disease. 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