Objective: The study aims to determine whether cystatin C is associated with HIV disease and HIV-associated neurocognitive impairment (NCI). Methods: Participants included 124 (HIV+ n = 77; HIV2 n = 47) older adults (age 50 years) examined at the University of California, San Diego HIV Neurobehavioral Research Program. Cystatin C, a biomarker of kidney functioning that has been linked to poor health outcomes, was measured in blood. Participants completed a comprehensive neurocognitive assessment that was used to define both global and domain NCI. Results: The HIV+ group had significantly higher cystatin C concentrations than the HIV2 group (d = 0.79 P , 0.001). Among HIV+ participants, those with NCI had higher cystatin C concentrations than those without NCI (d = 0.42, P = 0.055), particularly among participants taking tenofovir (d = 0.78, P = 0.004). A receiver-operator characteristic curve identified that cystatin C levels 0.75 mg/L were associated with NCI in the HIV+ group. Using this binary variable and including relevant covariates, multivariate modeling confirmed that NCI was associated with higher cystatin C levels (OR = 3.0; P = 0.03). Conclusions: Our results confirm that HIV+ older adults have higher cystatin C than HIV2 older adults and further identify that cystatin C may be associated with NCI in this population, particularly if they use tenofovir. This blood biomarker may be a useful clinical tool to identify older HIV+ persons at greater risk for cognitive decline.