HIV infection and HIV neurocognitive impairment are major global health problems. The prevalence of HIV associated neurocognitive disorders (HAND) is increasing as people with HIV are living longer due to the success of antiretroviral therapies. Our laboratory identified the soluble form of (sPrP(c)), the cellular non-pathogenic isoform of the prion protein, as a biomarker of HAND. In this review we discuss the published data addressing PrP(c) biology in normal conditions and pathologies, as well as the mechanisms of sPrP(c) shedding and secretion. Lastly, we discuss our studies that demonstrated that sPrP(c) is a biomarker of neurocognitive impairment in the HIV infected population.