Abstract Background: We aimed to investigate the association of lesion-specific epicardial adipose tissue (EAT) volume and density with the presence of lesion ischemia.Methods: We enrolled 45 patients (55 lesions) with known or suspected coronary artery disease who underwent coronary computed tomography angiography (CTA) followed by invasive fractional flow reserve (FFR) assessment within 30 days. EAT volume (index) and density in patient-, vessel- and lesion-level were measured on CTA images. Lesion-specific ischemia was defined as a lesion with stenosis diameter >90% or FFR ≤0.80. Multivariate analysis determined the independent association of EAT parameters with lesion ischemia. Results: Mean age of the patients was 60 years, and 75% were male. Overall, 55.6% of patients had ischemic lesions and a mean FFR baseline value of 0.82±0.10. Total EAT volume index was significantly higher in patients with functionally or anatomically significant stenosis. Specifically, peri-lesion EAT volume index, not the density, was positively correlated with lesion-specific ischemia independent of luminal stenosis and plaque characteristics (hazard ratio 1.56, 95% confidence interval 1.04–2.33, P=0.032; per 0.1 ml/m2 increase). Moreover, peri-lesion EAT volume was negatively correlated with lesion FFR values, whereas total EAT volume was positively correlated with fat accumulation and glucose metabolism. In addition, there was no association of EAT volume or density with lesion ischemia in vessel-level analysis.Conclusions: Lesion-specific EAT volume index, but not density, seems positively and independently associated with lesion ischemia, while its incremental diagnostic value of lesion ischemia should be further investigated.