The correlation of fractional flow reserve, which is presently the gold standard for evaluating myocardial ischemia, with three-dimensional quantitative coronary analysis-based quantitative flow ratio (QFR) is well-known. This study aims to evaluate the relationship of QFR after second-generation drug-eluting stent (2nd gen-DES) implantation to clinical outcomes. A total of 61 consecutive lesions, on which 2nd gen-DES implantation was performed from October 2014 to December 2015, were analyzed. Contrast-flow QFR (c-QFR) was obtained using reliable software (QAngio XA 3D) by modeled hyperemic flow velocity derived from coronary angiography without pharmacologically induced hyperemia. Clinical and angiographic data at the follow-up (18–30 months) were obtained from all cases. c-QFR measurement was possible in 52 (85%) lesions. Of these, clinically-driven target vessel revascularization (TVR) was performed in 8 (15%) lesions. Vessel c-QFR was significantly lower in the TVR group (0.703 ± 0.163 vs. 0.883 ± 0.103, p = 0.016). In the results of the receiver operating characteristics analysis for TVR, area under the curve for vessel c-QFR was 0.857. The cutoff point for the prediction of TVR was defined as vessel c-QFR of ≤ 0.82, the sensitivity of 88%, and specificity of 80%. Conclusion: Vessel c-QFR can predict TVR after 2nd gen-DES implantation. Further investigation is warranted to evaluate whether c-QFR guided coronary intervention ameliorates TVR rate.