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Background: Endothelial function may be improved by ticagrelor through adenosine-mediated mechanisms. We aimed to assess the effect of ticagrelor versus prasugrel on endothelial function in patients with stable coronary artery disease (CAD). Methods: In a prospective, randomized, crossover study, 22 stable CAD patients under prasugrel 10 mg once daily maintenance dose (MD) for at least 3 months were randomized to either ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with a direct treatment-crossover for another 15 days. Endothelial function was assessed by peripheral arterial tonometry (EndoPAT 2000 system, Itamar Medical, Caesarea, Israel) at Day 0 (randomization), Day 15, and Day 30. Reactive Hyperemia Index (RHI) was calculated by using an automated software, and endothelial dysfunction (ED) was defined as RHI <1.67. RHI at the end of the two treatment periods did not differ between ticagrelor and prasugrel MD treatments. Least squares estimates (95% confidence interval) were 1.78 (1.58-1.99) versus 1.88 (1.67-2.08), with a fixed estimate of −0.099 (95% CI: −0.45 to 0.25) for the difference between them (p = 0.5). ED rate did not differ significantly between ticagrelor and prasugrel (45.5% vs 45.5%, p = 0.6). Conclusions: In CAD patients, we have failed to find evidence of alteration of endothelial function following ticagrelor compared to prasugrel MD treatment, as assessed by peripheral arterial tonometry. Clinicaltrials.gov unique identifier: NCT01957540. Keywords: ticagrelor, endothelial function, P2Y12 inhibitors