To the Editor I read the article by De Giorgi and colleagues1 with great interest, and congratulate the authors on their excellent work. As the authors correctly state, this study is the first off-label study of which we are aware of propranolol for melanoma treatment.1 However, I would like to call attention to several points that need further clarification. Research has reported that propranolol inhibits melanoma growth in a U-shaped biphasic manner.2 Low propranolol doses lead to a significant melanoma growth inhibition, whereas higher doses are progressively less effective.2 There is also evidence that propranolol is metabolized via 4-hydroxylation by CYP2D6, a highly polymorphic enzyme, and that CYP2D6 genetic polymorphism has a significant effect on its pharmacokinetics.3 Furthermore, among the β-blockers, propranolol demonstrates a high level of inverse agonism4 and it can also act as a partial agonist, having important consequences on cancer cell proliferation, invasion, and migration.5 The findings of De Giorgi and colleagues add substantial information to previously published data, but evaluating these additional points would be useful for better improving the propranolol treatment of melanoma.