Patients with hypertrophic cardiomyopathy (HCM) are generally restricted regarding participation in competitive sports based on the potential risk of sudden cardiac death and malignant arrhythmias. As a result, they are often inactive and experience the negative consequences of a sedentary lifestyle. Hence, the need arises to strike the right balance between these 2 extremes through personalized exercise prescription. The aims of this study were (1) to assess the characteristics of patients with HCM practicing regular aerobic physical activity compared with sedentary patients; (2) to perform a personalized moderate-intensity exercise prescription and evaluate its effects. Patients with HCM were evaluated through clinical assessment, ECG, ambulatory ECG monitoring, echocardiography, and cardiopulmonary testing. A personalized moderate-intensity exercise prescription was performed, and the same investigations were repeated. Physically active patients with HCM demonstrated better cardiopulmonary functional capacity than sedentary patients (oxygen consumptionpeak/kg 32.9±7.4 versus 25.2±7.4 mL/min per kg P≤0.0001, ventilation/carbon dioxide production slope 26.7±4.3 versus 29.9±5.2 P=0.004), with similar prevalence of ventricular arrhythmias (P=0.43). Sedentary subjects showed a borderline higher prevalence of obesity (P=0.07) than physically active subjects. Moderate-intensity exercise prescription led to improved cardiopulmonary fitness without occurrence of adverse events. Patients with HCM practicing regular aerobic exercise have a better functional capacity in the absence of relevant events than sedentary patients. Conversely, a sedentary lifestyle led to a deterioration of cardiopulmonary functional capacity and fitness. The tailored moderate-intensity personalized exercise prescription appears to be a feasible approach in carefully selected patients with HCM to counterbalance the negative effects of sedentary behavior without significant major events.