Recent studies show that coronary microcirculatory impairment is an independent predictor of poor outcomes in patients with cardiovascular disease. However, controversy exists over whether microcirculatory resistance, a measure of coronary microcirculatory status, is dependent on epicardial stenosis severity. Previous studies demonstrating that microcirculatory resistance is dependent on epicardial stenosis severity have not accounted for collateral flow in their measurement of microcirculatory resistance. We investigated whether the index of microcirculatory resistance is independent of epicardial stenosis by comparing the index of microcirculatory resistance (IMR) levels in patients before and after percutaneous coronary intervention (PCI). Consecutive patients undergoing elective PCI of the left anterior descending artery were recruited. Patients who developed periprocedural myocardial infarction were excluded. A pressure-temperature sensor wire was used to measure the apparent IMR (IMR(app)), which does not adjust for collateral flow, and the true IMR (IMR(true)), which incorporates wedge pressure measurement to account for collateral flow, before and after PCI. In 43 patients, there was no difference between pre- and post-PCI IMR(true) (mean difference=0.8±11.7, P=0.675). IMR(app) was higher pre-PCI compared with post-PCI (mean difference=10.0±14.5, P<0.001). IMR(app) was higher than IMR(true) (mean difference=9.3±14.2, P<0.001), and the difference between the IMR(app) and IMR(true) became greater with decreasing fractional flow reserve and increasing coronary wedge pressure. Pre-PCI fractional flow reserve correlated modestly with IMR(app) (r=-0.33, P=0.03), but not IMR(true) (r=0.26, P=0.10). Coronary microcirculatory resistance is independent of functional epicardial stenosis severity when collateral flow is taken into account.