To determine the possible mechanism of the ischemic-like electrocardiogram (ECG) during exercise in the presence of anginal chest pain and normal coronary angiograms, both a treadmill exercise test (TET) and coronary hemodynamic study were prospectively performed in 33 consecutive patients (18 females and 15 males, aged 48 +/- 10 years) with angina of unknown cause. Although baseline characteristics and coronary hemodynamics were similar between patients with (TET+, n = 17) and those without (TET-, n = 16) ischemic-like ECG during TET, effort angina was more frequently seen in the former group (p < 0.01). Compared to TET- patients, TET+ patients had a significantly lower maximum great cardiac vein flow (GCVF, 108.8 +/- 47.0 vs 146.4 +/- 23.4 ml/min, p = 0.007), higher minimum coronary vascular resistance (0.94 +/- 0.41 vs 0.61 +/- 0.09 mmHg/ml/min., p = 0.003), and lower corrected GCVF (GCVF/rate-pressure product, 0.0087 +/- 0.0036 vs 0.0125 +/- 0.0019, p = 0.001) after dipyridamole infusion (0.56 mg/kg for 4 min). Though coronary flow reserve was significantly lower in TET+ than in TET- patients (2.26 +/- 0.59 vs 3.08 +/- 0.48, p = 0.0001), myocardial oxygen consumption and myocardial efficiency (rate-pressure product/myocardial oxygen consumption) were still similar between these two groups after dipyridamole infusion. Thus, coronary microvascular dysfunction rather than altered cardiac metabolism could contribute to effort angina and ischemic-like ECG during exercise in patients with anginal chest pain and normal coronary angiograms.