Background: In this study, lesion flow coefficient (LFC: ratio of % area stenosis [%AS] to the square root of the ratio of the pressure drop across the stenosis to the dynamic pressure in the throat region), that combines both the anatomical (%AS) and functional measurements (pressure and flow), was assessed for application in a clinical setting. Methods and results: Pressure, flow, and anatomical values were obtained from patients in 251 vessels from two different centers. Fractional flow reserve (FFR), Coronary flow reserve (CFR), hyperemic stenosis resistance index (HSR) and hyperemic microvascular index (HMR) were calculated. Anatomical data was corrected for the presence of guidewire and the LFC values were calculated. LFC was correlated with FFR, CFR, HSR, HMR, individually and in combination with %AS. The p < 0.05 was used for statistical significance. LFC correlated significantly when the FFR (pressure-based), CFR (flow-based), and anatomical measure %AS were combined (r = 0.64; p < 0.05). Similarly, LFC correlated significantly when HSR, HMR, and %AS were combined (r = 0.72; p < 0.05). LFC was able to significantly (p < 0.05) distinguish between the two concordant and the two discordant groups of FFR and CFR, corresponding to the clinically used cut-off values (FFR = 0.80 and CFR = 2.0). The LFC could also significantly (p < 0.05) distinguish between the normal and abnormal microvasculature conditions in the presence of non-significant epicardial stenosis, while the comparison was borderline significant (p = 0.09) in the presence of significant stenosis. Conclusion: LFC, a parameter that combines both the anatomical and functional end-points, has the potential for application in a clinical setting for CAD evaluation.