Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. The objective of the present study was to investigate the effectiveness of intravenous (IV) nicorandil infusion for fractional flow reserve (FFR) measurement. In this crossover randomized study, 49 patients underwent FFR measurement with a consecutive randomized order of patient-blind infusions of continuous IV adenosine administration and a single bolus IV administration of nicorandil. The primary endpoint was the difference between the FFR by nicorandil and the FFR by adenosine, as assessed by the Bland–Altman method. The mean FFR value measured by nicorandil was not significantly different from that measured by adenosine [0.8125 ± 0.1349 vs. 0.7978 ± 0.124; mean difference, 0.0147 (95% confidence interval − 0.0373, 0.0667); P = 0.58]. There was no clinically significant diagnostic discordance, with the FFR by nicorandil > 0.80 and that by adenosine < 0.75. Hyperemia was achieved earlier using nicorandil than adenosine (34 ± 13 vs. 58 ± 15, P < 0.001). The duration of hyperemia after IV nicorandil was variable (6–570 s, mean 89 ± 98 s). IV nicorandil decreased systolic blood pressure by 32 ± 16 mm Hg (24 ± 10%) from baseline. Linear regression analysis showed that the average FFR value and the difference in systolic blood pressure were significantly associated with the bias in the FFR value between the two drugs. In conclusions, the results of the present study suggest that IV nicorandil can achieve maximal hyperemia easily and rapidly, providing an acceptable diagnostic performance for FFR assessment. However, a wide range of variation in hyperemic plateau and a decrease in blood pressure are the major limitations of this method.