The means by which epicardial adipose tissue (EAT) could influence coronary plaque progression biologically remain unclear. We investigated the association between the histological findings of EAT and coronary plaque characteristics assessed by coronary computed tomography angiography (CCTA). We enrolled 34 patients in whom one or more coronary plaques containing non-calcified components were detected on CCTA before cardiac surgery [coronary artery bypass graft (CABG) or non-CABG]. We evaluated visceral adipose tissue (VAT) area, EAT volume, and coronary plaque characteristics including minimum computed tomography density (CTD) and vascular Remodeling Index (RI). Lower CTD and higher RI were considered as high-risk characteristics, and coronary plaque with both CTD < 39 Hounsfield units and RI > 1.05 was defined as two-characteristic plaque (2-CP). The numbers of CD68⁺ macrophages and CD31⁺ microvessels were assessed in six random high-power fields (400×) of EAT samples obtained during cardiac surgery. The entire cohort showed a wide range of EAT volume, which were similar between patients with 2-CP and those without. Patients with 2-CP had more amounts of EAT macrophages (85 ± 38 versus 45 ± 22, p = 0.0005) and vascularity (62 ± 33 versus 37 ± 19, p = 0.013) than those without. On multivariate analyses adjusted for age, sex, coronary risk factors, statin use, type of surgery, VAT area, EAT volume, and coronary calcium score, the presence of 2-CP showed significant correlation with increased EAT macrophages (β = 0.65, p = 0.014) and vascularity (β = 0.74, p = 0.0053). Our findings support the hypothesis that EAT biologic activities are associated with coronary plaque vulnerability.