This study aimed to investigate the association between perivascular fat attenuation index (FAI) and hemodynamic significance of coronary lesions. Patients with stable angina who underwent coronary computed tomography (CT) angiography and invasive fractional flow reserve (FFR) measurement within 2 weeks were retrospectively included. Lesion-based perivascular FAI, high-risk plaque features, total plaque volume (TPV), machine learning-based FFRCT, and other parameters were recorded. Lesions with invasive FFR ≤ 0.8 were considered functionally significant. This study included 167 patients with 219 lesions. Diameter stenosis (DS), lesion length, TPV, and perivascular FAI were significantly larger or longer in the group of hemodynamically significant lesions (FFR ≤ 0.8). In addition, smaller FFRCT value was associated with functionally significant lesions (0.720 ± 0.11 vs 0.846 ± 0.10, p < 0.001). No significant difference was found between the hemodynamically significant and insignificant subgroups with respect to CT-derived high-risk plaque features. According to multivariate analysis, DS, TPV, and perivascular FAI were significant predictors of lesion-specific ischemia. When integrating DS, TPV, and perivascular FAI, the area under the curve (AUC) of this combined method was 0.821, which was similar to that of FFRCT (AUC, 0.821 vs 0.850; p = 0.426). The diagnostic accuracy of FFRCT was higher than that of the combined approach, but the difference was statistically insignificant (79.0% vs 74.0%, p = 0.093). Perivascular FAI was significantly higher for flow-limiting lesions than for non-flow-limiting lesions. The combined use of FAI, TPV, and DS could predict ischemic coronary stenosis with high diagnostic accuracy. • Perivascular FAI was significantly higher for flow-limiting lesions than for non-flow-limiting lesions. • Combined use of FAI, plaque volume, and DS provided diagnostic performance comparable to that of machine learning-based FFR CTfor predicting ischemic coronary stenosis. • No significant difference was found between the hemodynamically significant and insignificant subgroups with respect to CT-derived high-risk plaque features.