Nitric oxide (NO) is a biologically active inorganic molecule involved in the regulation of many physiological processes, such as control of blood flow, platelet adhesion, endocrine function, neurotransmission and neuromodulation. In the present study, for the first time, we investigated the modulation of NO signaling in platelets of HD patients. We recruited 55 patients with manifest HD and 28 gender- and age-matched healthy controls. Our data demonstrated that NO-mediated vasorelaxation, when evoked by supernatant from insulin-stimulated HD platelets, gradually worsens along disease course. The defective vasorelaxation seems to stem from a faulty release of NO from platelets of HD patients and, it is associated with impairment of eNOS phosphorylation (Ser(1177)) and activity. This study provides important insights about NO metabolism in HD and raises the hypothesis that the decrease of NO in platelets of HD individuals could be a good tool for monitoring advanced stages of the disease.