Background-Although no data exist on the effect of altitude exposure on coronary flow reserve (CFR), patients with coronary artery disease (CAD) are advised not to exceed moderate altitudes of Ϸ2500 m above sea level. We studied the influence of altitude on myocardial blood flow (MBF) in controls and CAD patients. Methods and Results-In 10 healthy controls and 8 patients with CAD, MBF was measured by positron emission tomography and 15 O-labeled water at rest, during adenosine stress, and after supine bicycle exercise. This protocol was repeated during inhalation of a hypoxic gas mixture corresponding to an altitude of 4500 m (controls) and 2500 m (CAD). Workload was targeted to comparable heart rate-blood pressure products at normoxia and hypoxia. Resting MBF increased significantly in controls at 4500 m (ϩ24%, PϽ0.01) and in CAD patients at 2500 m (ϩ24%, PϽ0.05). Altitude had no influence on adenosine-induced hyperemia and CFR. Exercise-induced hyperemia increased significantly in controls (ϩ38%, PϽ0.01) at 4500 m (despite a reduction in workload, Ϫ28%, PϽ0.0001) but not in CAD patients at 2500 m (moderate decrease in workload, Ϫ11%, PϽ0.05). Exercise-induced reserve was preserved in controls (ϩ10%, PϭNS) but decreased in CAD patients (Ϫ18%, PϽ0.005). Conclusions-At 2500 m altitude, there is a significant decrease in exercise-induced reserve in CAD patients, indicating that compensatory mechanisms might be exhausted even at moderate altitudes, whereas healthy controls have preserved reserve up to 4500 m. Thus, patients with CAD and impaired CFR should be cautious when performing physical exercise even at moderate altitude.