Abstract Background The clinical importance of physiological distribution of coronary atherosclerosis is emerging. However, this concept has limited clinical application because of complex formulas and technical difficulties in measurement. Purpose We aimed to evaluate the utility of a simple physiological metric using pressure drop across the lesion, through the analysis of association with hemodynamic and plaque characteristics. Methods The analysis was conducted on a total 246 lesions in 136 vessels from DISCOVER-FLOW study, which was the first-in-human, prospective, international, multi-center study demonstrating the diagnostic accuracy of coronary computational tomographic angiography (CCTA)-derived fractional flow reserve (FFRCT) for invasive FFR. All vessel- and lesion-level hemodynamic as well as plaque parameters were analyzed by independent core laboratories using CCTA and computational fluid dynamic techniques. Functional significance (FS) was defined as CTA-derived FFR (FFRCT) ≤ 0.80, and physiological focal disease (PFD) was defined as change in FFRCT across the lesion (ΔFFRCT) ≥ 0.06 and FFR drop across the lesion ≥ 0.0015/mm. The lesions were categorized into four groups based on the existence of FS and/or PFD and denoted as follows: FS(-) PFD(-) for group A, FS(-) PFD(+) for group B, FS(+) PFD(-) for group C, FS(+) PFD(+) for group D; Statistics of hemodynamic and plaque characteristics among the four groups were compared. Results 48.8% and 54.5% of total lesions were designated as FS and PFD, respectively. Vessel-level characteristics such as total plaque volume (TPV) of vessel and percent atheroma volume (PAV) of vessel were positively associated with FS (all p<0.001 for A vs C and B vs D). In the lesion level, wall shear stress (WSS) was higher when PFD was present, regardless of FS (136.5 vs 260.8, p<0.001 with A vs B; 125.6 vs 299.9, p<0.001 with C vs D, Figure panel a). Plaque burden at minimal lumen area (PB) was significantly greater with PFD in both negative FS and positive FS (52.3 vs 68.5, p<0.001 with A vs B; 49.5 vs 81.1, p<0.001 with C vs D, Figure panel b). Other volumetric plaque factors such as plaque volume (PV) and PAV, were also significantly greater with PFD in both negative FS and positive FS (all p<0.01 for A vs B and C vs D, Figure panel c and d). Adverse plaque characteristics (APC) were found to be frequently present in conjunction with PFD, regardless of FS (30.0% vs 53.6%, p=0.013 with A vs B; 26.2% vs 68.0%, p<0.001 with C vs D, Figure panel e). PFD without FS showed significantly higher in all hemodynamic and plaque characteristics compared to FS without PFD (B vs C - p<0.001 for WSS, PV, PAV; p=0.002 for PB; p=0.012 for APC, Figure). Conclusions Hemodynamic and morphological characteristics related to plaque vulnerability were associated with a pressure drop-derived index, PFD, independent of functional significance of the vessel.