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Hyperspectral imaging (HSI) is a technology that with limited training can noninvasively measure oxygenated hemoglobin (oxyHb) and deoxygenated hemoglobin concentrations in the skin to create an oxygenation map. This pilot study determined whether HSI could be used to demonstrate vascular dysfunction in the upper extremity of patients with peripheral artery disease (PAD) and coronary artery disease (CAD).This prospective study included 93 consecutive, consented patients presenting to the vascular clinic, with and without diagnosed arterial disease, and healthy volunteers. Patients underwent HSI at the upper arm, forearm, and palm before and after cuff occlusion (50 mm Hg above systolic) for 5 minutes. Medical records of enrolled patients were reviewed for demographic data, medications, surgical history, and other pertinent information.Significant changes occurred with oxyHb, with minimal to no effects on deoxygenated hemoglobin. The highest values of oxyHb were detected in the upper arm, followed by the forearm and hand. The absolute and percentage change in oxyHb measured in the upper arm and forearm was significantly reduced in controls aged >40 years compared with controls aged <40 years. Significant differences were noted in the upper arm oxyHb absolute change in response to cuff occlusion comparing PAD or CAD (n = 47) vs the older control cohort (P= .028). When the 23 patients with PAD only were separated out, the upper arm oxyHb response to cuff occlusion is even more significantly impaired (P< .01) compared with controls.Our study suggests the ability of HSI to assess the presence of PAD or CAD based on systemic vascular dysfunction at sites remote from the clinically diseased vascular bed. This could enable early screening and tracking of arterial disease patients before the development of clinically advanced disease.