Identification of hypertrophic cardiomyopathy (HC) in young athletes is challenging when left ventricular (LV) wall thickness is between 13 and 15 mm. The aim of this study was to revise the ability of simple echocardiographic and clinical variables for the differential diagnosis of HC versus athlete's heart. Twenty-eight athletes free of cardiovascular disease were compared with 25 untrained patients with HC, matched for LV wall thickness (13 to 15 mm), age, and gender. Clinical, electrocardiographic, and echocardiographic variables were compared. Athletes had larger LV cavities (60 ± 3 vs 45 ± 5 mm, p <0.001), aortic roots (34 ± 3 vs 30 ± 3 mm, p <0.001), and left atria (42 ± 4 vs 33 ± 5 mm, p <0.001) than patients with HC. LV cavity <54 mm distinguished HC from athlete's heart with the highest sensitivity and specificity (both 100%, p <0.001). Left atrium >40 mm excluded HC with sensitivity of 92% and specificity of 71% (p <0.001). Athletes showed higher e′ velocity by tissue Doppler imaging than patients with HC (12.5 ± 1.9 vs 9.3 ± 2.3 cm/second, p <0.001), with values <11.5 cm/second yielding sensitivity of 81% and specificity of 61% for the diagnosis of HC (p <0.001). Absence of diffuse T-wave inversion on electrocardiography (specificity 92%) and negative family history for HC (specificity 100%) also proved useful for excluding HC. In conclusion, in athletes with LV hypertrophy in the “gray zone” with HC, LV cavity size appears the most reliable criterion to help in diagnosis, with a cut-off value of <54 mm useful for differentiation from athlete's heart. Other criteria, including LV diastolic dysfunction, absence of T-wave inversion on electrocardiography, and negative family history, further aid in the differential diagnosis.