Synaptic damage, a prevalent result despite viral suppression with antiretroviral therapy, is a pathological characteristic of neurological impairment in people infected with human immunodeficiency virus (HIV, PLWH) (ART). Synaptic density measurement in humans could help researchers better understand HIV neuropathogenesis and provide a dynamic biomarker for clinical trials. In PLWH and HIV-uninfected subjects, the researchers used new synaptic vesicle protein 2A (SV2A) positron emission tomographic (PET) imaging to evaluate synaptic density in the frontostriatalthalamic area. 13 older male PLWH on ART underwent MRI and PET scans with the SV2A ligand [11C]UCB-J with partial volume correction, as well as neuropsychological assessments, in this cross-sectional pilot investigation. The frontostriatalthalamic circuit’s SV2A binding potential (BPND) was compared to 13 HIV-uninfected subjects of similar age and neurocognitive function in PLWH. When compared to HIV-uninfected people, PLWH had a 14% lower frontostriatalthalamic SV2A synaptic density (PLWH: mean [SD], 3.93 [0.80]; HIV-uninfected: 4.59 [0.43]; P=.02, effect size 1.02). In an exploratory analysis, differences were found in a variety of additional locations. In PLWH, higher frontostriatalthalamic SV2A BPND was linked with superior grooved pegboard performance (r=0.61, P=.03), a measure of motor coordination. In a pilot investigation, SV2A PET imaging revealed lower synapse density in the frontostriatalthalamic circuit and other cortical areas in older male PLWH on ART compared to HIV-uninfected. To assess whether disparities in PLWH are due to HIV or comorbidities, larger studies controlling for factors other than age were needed. SV2A imaging has shown to be a promising biomarker for HIV neuropathogenesis research and therapeutic approaches.