Homogeneity of microvascular resistance in different perfusion areas of the same heart is generally assumed. We investigated the effect of the severity of an epicardial stenosis on microvascular resistance in 27 patients with coronary artery disease and stable angina. All patients had an angiographically normal coronary artery, an artery with an intermediate lesion, and an artery with a severe lesion; the latter was treated with angioplasty. In each patient, distal blood flow velocity and pressure were measured during baseline and maximal hyperemia (induced by intracoronary adenosine) using a Doppler and pressure guide wire, respectively. The ratio of mean distal pressure to average peak blood flow velocity was used as an index for the microvascular resistance (MR_v). Within patients, the hyperemic MR_v was higher in arteries with more severe stenosis ( P = 0.021). After percutaneous transluminal coronary angioplasty (PTCA), the hyperemic MR_v decreased (pre-PTCA, 2.6 vs. post-PTCA, 1.9 mmHg·cm^–1s^–1, P < 0.01) toward the value of the reference artery (1.7 mmHg·cm^–1s^–1; P = 0.67). We conclude that there is a positive association between coronary lesion severity and variability of distal microvascular resistance that normalizes after angioplasty. This study challenges the concept of uniform distribution of hyperemic MR_v that is relevant for the interpretation of both noninvasive and invasive diagnostic tests.