Functional lesion assessment for coronary tandem lesions and its clinical applications have not been thoroughly studied. The aim of this study was to test the hypothesis that the fractional flow reserve (FFR) gradient across an individual stenosis (ΔFFR) during pressure-wire pullback is a surrogate of the relative functional severity of each stenosis in coronary tandem lesions. For in vitro validation, computational flow dynamic modeling of coronary tandem lesion with various degree of stenosis was constructed. For clinical validation, a total of 52 patients (104 lesions) with coronary tandem lesions (2 stenoses along 1 coronary artery) were consecutively enrolled, and tailored stent procedures based on ΔFFR was performed, at first treating the lesion with large ΔFFR and then subsequently reassessing the FFR for the remaining lesion. The coronary stenosis was considered functionally significant and stenting was performed when the FFR of a lesion was ≤0.80. Using in vitro computational flow dynamic modeling, the lesion with the large ΔFFR of the coronary tandem lesion was indicated as the lesion with the greater degree of simulated diameter stenosis. In the clinical cohort, 28 patients (53.8%) had only single-lesion treatment, and stent implantation for 28 lesions (26.9%) was deferred according to the proposed strategy. During the 9-month follow-up period, only 1 repeat revascularization occurred among the deferred lesions. In conclusion, for the treatment of coronary tandem lesions, ΔFFR may be a useful index for prioritizing the treatment sequence and optimizing the stenting procedure. In this way, unnecessary stent implantation can be avoided, with the achievement of favorable functional and clinical outcomes.