Abstract Background The functional severity and morphological features of epicardial lesions are both related to plaque vulnerability and adverse coronary events. However, their relationship remains controversial, especially in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Purpose This study aimed to examine whether quantitative flow ratio (QFR), an angiography-based computation of fractional flow reserve, was associated with optical coherence tomography (OCT)-defined vulnerable plaques such as thin-cap fibroatheromas (TCFAs) in a board spectrum of population, including patients presenting stable angina and NSTE-ACS. Methods We identified patients who underwent OCT examinations from 2 prospective cohorts and then assessed interrogated vessels with QFR. Lesions were divided into tertiles: QFR-T1 (QFR <0.85)<qfr),>, QFR-T2 (0.85 to 0.93) and QFR-T3 (QFR >0.93). Results This post-hoc analysis included 83 lesions from 79 patients (mean age: 61.5±9.8 years, males: 58%). Patients with NSTE-ACS accounted for the majority of the population (67%). The median % diameter stenosis and median QFR value were 42% (36 to 49%) and 0.88 (0.83 to 0.95), respectively. The prevalence of OCT-TCFA was significantly higher in QFR-T1 (50%) than in QFR-T2 (14%) and QFR-T3 (19%) (p=0.003 and 0.018, respectively). Overall significant differences were observed among tertiles in maximum lipid arc, thinnest fibrous cap thickness (FCT), and minimal lumen area (MLA) (p=0.017, 0.040, and <0.001, respectively). The Spearman's correlation analysis showed that QFR was significantly related to MLA (ρ = 0.537, p<0.001), % area stenosis (ρ = –0.512, p<0.001), maximum lipid arc (ρ = –0.360, p=0.002), lipid length (ρ = –0.242, p=0.038), lipid index (ρ = –0.333, p=0.004), and thinnest FCT (ρ = 0.315, p=0.006). In the multivariable analysis, QFR ≤0.80 remained as a significant determinant of TCFAs regardless of the presence of NSTE-ACS and the level of low-density lipoprotein cholesterol (adjusted odds ratio = 4.387, 95% confidence interval: 1.297 to 14.839, p=0.017). In addition, QFR demonstrated moderate predictive ability for OCT-TCFA (area under the curve = 0.72, 95% confidence interval: 0.58 to 0.86, p=0.003) with the best cutoff of ≤0.86 (sensitivity: 65%; specificity: 73%; negative predictive value: 85%; accuracy: 71%). Conclusions Lower QFR was related to OCT-TCFA and other vulnerable plaque characteristics in angiographically mild-to-intermediate stable lesions and culprit lesions from NSTE-ACS. The QFR might be a useful tool for ruling out high-risk, rupture-prone plaques without using any pressure wires or vasodilators. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Jiangsu Provincial Key Research and Development Program Flow diagram of patient selectionOCT findings according to QFR tertiles