Background: Fractional fow reserve (FFR) is, next to lesion severity, affected by plaque vulnerability as assessed by coronary computed tomography angiography (CCTA) and associated with imminent acute coronary syndromes. Instantaneous wave-free ratio (iFR) has recently emerged as an alternative for FFR to interrogate coronary lesions for ischemia. It is, however, unknown whether vasodilator free assessment with iFR is associated with plaque stability similarly as FFR. The current substudy of the PACIFIC trial explores the impact of CCTA derived unfavorable plaque features on both hyperemic and non-hyperemic fow indices in order to detect vulnerable plaques. Methods: Of 119 patients (62% men, age 58 ± 8.6 years) with suspected coronary artery disease, 257 vessels were prospectively evaluated. Each patient underwent 256-slice CCTA to assess stenosis severity and plaque features (positive remodeling (PR), low attenuation plaque (LAP), spotty calcifcation (SC) and napkin ring sign (NRS)), as well as intracoronary pressure measurements (FFR, iFR, resting Pd/Pa and pressure ratio during adenosine within the wave-free period (iFRa)). CCTA derived plaque characteristics were related to these invasive pressure measurements. Results: Atherosclerotic plaques were present in 170 (66%) coronary arteries. On a per-vessel basis, luminal stenosis severity was signifcantly associated with impaired FFR, iFR, resting Pd/Pa and iFRa. Multivariable analysis revealed that PR and LAP were independently related to an impaired FFR (p = 0.006 and p = 0.038, respectively) and iFRa (p = 0.005 and p = 0.027, respectively), next to stenosis severity (p <0.001 for all). Conversely, these adverse plaque characteristics were not related to the vasodilator free parameters iFR and Pd/Pa. Conclusion: CCTA derived vulnerable plaque characteristics are associated with detrimental hyperemic fow indices as assessed with FFR and iFRa, but not with non-hyperemic indices as defined by iFR and resting Pd/Pa. These findings suggest that induction of hyperemia is mandatory to reveal plaque vulnerability during hemodynamic interrogation of a coronary artery.