Objective Measuring the fractional flow reserve (FFR) requires the induction of coronary hyperemia, usually with adenosine, adenosine triphosphate (ATP), or papaverine. However, adenosine can induce rhythmic complications, and intracoronary boluses of papaverine that prolong the QT interval can cause ventricular tachycardia. Injection of contrast media, which is routinely performed to validate the FFR guidewire placement, also induces hyperemia and may be an alternative method of measuring the FFR. We evaluated the diagnostic accuracy of the FFR after contrast hyperemia (FFRcont) compared to FFR evaluated after intracoronary papaverine (FFRpp). Methods This study included 109 lesions in 93 patients (mean age 70.4±8.7 years) with stable coronary disease. The FFR was measured as follows: 1) baseline pressure value; 2) FFRcont after intracoronary contrast injection (iopamidol, 8 mL for left coronary artery [LCA] or 6 mL for right coronary artery [RCA]); 3) FFRpp after intracoronary injection of papaverine (12 mg for LCA or 8 mg for RCA). Results FFRcont values were strongly correlated with FFRpp (R=0.940, p<0.0001; FFRpp = FFRcont ×1.007-0.032). The best cut-off point in the receiver operator curve analysis for predicting a FFRpp <0.80 was 0.82 (area under the curve =0.980; sensitivity 95.1%, specificity 91.2%, positive predictive value 86.7%, negative predictive value 96.9%). Conclusion FFRcont is highly accurate for predicting FFRpp. An FFRcont threshold value of 0.82 provides excellent sensitivity and a negative predictive value. FFRcont is an alternative method of inducing hyperemia.