Fractional flow reserve (FFR), the ratio of the pressures distal (Pd) and proximal (Pa) to a stenosis, and coronary flow reserve (CFR), the ratio of flows at maximal vasodilation to the resting condition, are widely used for determining the functional severity of a coronary artery stenosis. However, the diameter of the native artery might influence the FFR values. Therefore, using an in-vitro experimental study, we tested the variation of FFR for two arterial diameters, 2.5 mm (N1) and 3 mm (N2). We hypothesize that FFR is not influenced by native arterial diameter. For both N1 and N2, vasodilation-distal perfusion pressure (CFR-Prh) curves were obtained using a 0.35 mm guidewire by simulating physiologic flows under different blockage conditions: mild (64% area stenosis (AS)), intermediate (80% AS) and severe (90% AS). The FFR values for the two arterial models differed insignificantly, within 3%, for mild and intermediate stenoses but differed appreciably for severe stenosis (∼25%). This significant difference in FFR values for severe stenosis can be attributed to relatively larger difference in guidewire obstruction effect at the stenotic throat region of the two native arterial models. These findings confirm that FFR will not differ for the clinically relevant cases of mild and intermediate stenosis for different arterial diameters.