Background: Coronary flow reserve (CFR) reflects the functional capacity of microcirculation to adapt to blood demand during increased cardiac work. In this study, CFR of hemodialysis patients with angiographically normal coronary arteries was evaluated using transthoracic second harmonic Doppler echocardiography. Methods and Results: Ten hemodialysis patients, and 14 sex-, age- and left ventricular mass index-matched hypertensive controls with angiographically normal coronary arteries underwent transthoracic second harmonic Doppler echocardiographic examination. Coronary basal diastolic peak flow velocities and hyperemic peak flow velocities after dipyridamole infusion (0.56 mg/kg over 4 min) were measured. CFR was defined as the ratio of hyperemic to basal diastolic peak velocities. CFR ≧2.0 was regarded as normal. Additionally, Doppler tissue imaging pulse wave measurements were taken from the lateral and septal corners of the mitral annulus. CFR values were significantly lower in the study group than in the control group (2.03 ± 0.3 vs. 2.61 ± 0.5, p = 0.005). In 5 of 10 hemodialysis patients, CFR was <2.0 (50%), however in only 1 of 14 control patients it was <2.0 (5%). Conclusions: Impairment of coronary microvasculature occurs earlier in patients with chronic renal failure and may be the harbinger of subsequent primary uremic myocardial disease. In patients with chronic renal failure and normal coronary arteries, decreased CFR by transthoracic echocardiography might be regarded as an early finding of an affected coronary vasculature.