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To quantitatively measure brain glucose metabolism in treated HIV-positive individuals with [18F]-labeled fluorodeoxyglucose (FDG) PET/CT.We performed a cross-sectional comparison of FDG uptake in 47 treated HIV+ individuals, 10 age-matched controls (HIV−) sharing many of the comorbid conditions seen in the HIV+ group, and 19 age-matched healthy controls (HCs). We compared whole-brain (WB) and regional FDG standardized uptake values (SUVs) of select subcortical/central structures among the groups and correlated the values to clinical and neuropsychological assessments. A variable selection model was used to predict SUVs in HIV+ (n = 47) and in combined HIV+ and HIV− participants (n = 57).We found lower WB SUVmax in HIV+ participants compared to HCs but not to HIV− participants. Among the relative SUVmean measurements (regional SUVmean/WB SUVmean), only relative thalamic uptake values were lower in HIV+ compared to HIV− participants. When HIV+ and HIV− participants were grouped, cardiovascular disease risk scores best predicted WB SUVmean and SUVmax, while HIV status best predicted thalamic relative SUVmean.We identified an important role for cardiovascular disease in neuronal loss/dysfunction, as measured by FDG-PET, in treated HIV+ patients. This underscores the need for shifting the focus of clinical intervention in this vulnerable population from HIV effects alone to a wider set of comorbid conditions, mainly cardiovascular disease. Only the thalamus showed significantly lower relative uptake in the HIV+ compared to the HC and HIV− groups. This needs to be further evaluated for underlying pathophysiology and potential association with memory, executive functioning, and attention deficits seen in the HIV+ population.