Background - Ischemia occurs frequently in hypertrophic cardiomyopathy (HCM) without evidence of epicardial stenosis. This study evaluates the hypothesis that the occurrence of ischemia in HCM is related to remodeling of the coronary microcirculation. Methods and Results - End-diastolic septal wall thickness was significantly increased in patients with HCM (25.8±2.9 mm) in comparison with cardiac transplant recipients (control subjects: 11.4±3.0 mm; P<0.05). Although the diameter of the left anterior descending coronary artery was similar in both groups (3.0±0.8 versus 3.0±0.5 mm, P=NS), the coronary resistance reserve (CRR=CRR(basal)/CRR(hyperemic)), corrected for extravascular compression (end-diastolic left ventricular pressure), was reduced to 1.5±0.6 in HCM (P<.05; control, 2.6±0.8). Arteriolar lumen (AL) divided by wall area was lower in HCM (21±5% versus 30±4%; P<.05), and capillary density tended to decrease (from 1824±424 to 1445±513 per mm2, P=.11) in HCM. CRR was linearly related to normalized AL according to the formula CRR=0.1 AL-0.45 (r=.57; P<.05). Further analysis revealed that CRR, AL, and capillary density were all linearly related to the degree of hypertrophy. Conclusions - Decrements in CRR were related to changes of the coronary microcirculation. Both the decrease in CRR and these changes in the coronary microcirculation were related to the degree of hypertrophy. All these factors might contribute to the well-known occurrence of ischemia in this patient group.