Abstract Objectives This study investigated sex differences in coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients with angina in the absence of obstructive coronary artery disease. Background Coronary microvascular dysfunction is associated with worse long-term outcomes, especially in women. Coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) are 2 methods of assessing the coronary microcirculation. Methods We prospectively enrolled 117 women and 40 men with angina in the absence of obstructive coronary artery disease. We performed CFR, IMR, fractional flow reserve, and quantitative coronary angiography in the left anterior descending artery. Coronary flow was assessed with a thermodilution method by obtaining mean transit time (Tmn ) (an inverse correlate to absolute flow) at rest and hyperemia. Results All patients had minimal atherosclerosis by quantitative coronary angiography (% diameter stenosis: 23.2 ± 12.3%), and epicardial disease was milder in women (fractional flow reserve: 0.88 ± 0.04 vs. 0.87 ± 0.04; p = 0.04). IMR was similar between the sexes (20.7 ± 9.8 vs. 19.1 ± 8.0; p = 0.45), but CFR was lower in women (3.8 ± 1.6 vs. 4.8 ± 1.9; p = 0.004). This was primarily due to a shorter resting Tmn in women (p = 0.005), suggesting increased resting coronary flow, whereas hyperemic Tmn was identical (p = 0.79). In multivariable analysis, female sex was an independent predictor of lower CFR and shorter resting Tmn. Conclusions Despite similar microvascular function in women and men by IMR, CFR is lower in women. This discrepancy appears to be due to differences in resting coronary flow between the sexes. The effect of sex differences should be considered in interpretation of physiological indexes using resting coronary flow.