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Background: Despite the complexity of SYNTAX score (SS), guidelines recommend this tool to help choosing between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with left main of three-vessel coronary artery disease. The aim of this study was to compare the inter-observer variation in SS performed by clinical cardiologists (CC), interventional cardiologists (IC), and cardiac surgeons (CS). Methods: Seven coronary angiographies from patients with left main and/or three-vessel disease chosen by a heart team were analyzed by 10 CC, 10 IC and 10 CS. SS was calculated via SYNTAX website. Results: Kappa concordance was very low between CC and CS (k = 0.176), moderate between CS and IC (k = 0.563), and moderate between CC and IC (0.553). There was a statistically significant difference between CC, who classified more cases as low complexity (70%), and CS, who classified more cases as moderate complexity (80%) ( p  = 0.041). Conclusion: Concordance between SS analyzed by CC, CS and IC is low. The usefulness of SS in decision-making of revascularization strategy is undeniable and evidence supports its use. However, this study highlights the importance of well-trained professionals on calculating the SS. It could avoid misclassification of borderline cases.