OBJECTIVE A significant proportion of women with angina-like chest pain and angiographically normal coronary arteries have microvascular dysfunction as detected by reduced coronary blood flow reserve (CFR). Classical clinical risk factors of atherosclerosis poorly predict this scenario. We sought to assess whether increased epicardial fat tissue, which is a metabolically active organ, could be associated with impaired CFR in these patients. METHODS We enrolled 68 women who underwent coronary angiography and had no obstructive coronary artery disease. Data about classical risk factors, insulin resistance and serum levels of C-reactive protein (CRP) and adiponectin were obtained. Stress tests were evaluated. Coronary flow velocities at baseline and under-induced hyperemia and epicardial fat thickness (EFT) were measured by transthoracic echocardiography within 48 h of angiography. CFR >or=2.0 was considered normal. RESULTS Forty percent of women had reduced CFR suggestive of microvascular dysfunction and 60% had normal CFR. Menopause, hypertension and abnormal stress tests were significantly more prevalent, adiponectin level was significantly decreased, CRP, insulin resistance, and EFT were significantly increased in women with microvascular dysfunction as compared with those without. On multivariate regression analysis EFT emerged as the only independent predictor of microvascular dysfunction (P<0.0001). EFT of >0.45 cm had 85% sensitivity and 75% specificity to detect CFR <2 (P<0.0001). Traditional risk factors for atherosclerosis did not predict women with abnormal microvascular function. CONCLUSIONS EFT has the potential to be an additional and easy diagnostic tool for risk stratification of women with chest pain and angiographically normal coronary arteries.