The aim of this study is to assess the relationship of epicardial adipose tissue (EAT) and plaque vulnerability. We consecutively enrolled 82 patients with coronary artery disease (CAD). A symptom-related vessel was imaged by virtual histology intravascular ultrasound (VH-IVUS). In 60 out of 82 patients, all three vessels were studied by VH-IVUS. EAT thickness was measured by echocardiography. All patients were divided into thick (≥3.5 mm) and thin EAT groups (<3.5 mm). VH-IVUS parameters were compared according to the EAT group. To evaluate the independent effect of EAT thickness on plaque vulnerability, a set of well-known CAD risk factors and EAT thickness were included in multiple linear regression models of VH-IVUS parameters which denotes plaque vulnerability. In a symptom-related vessel analysis, the thick EAT group had significantly more thin-cap fibroatheromas (TCFAs). In a symptom-related vessel analysis among 62 patients with unstable angina out of 82 patients, the thick EAT group had significantly more thin-cap fibroatheromas (TCFAs). In all three vessels analysis, the thick EAT group was associated with significantly larger total plaque volume, higher total plaque volume index, higher mean plaque burden, higher plaque volume indexes of the necrotic core (NC), and more total number of TCFAs than the thin EAT group. By multivariate analysis, total TCFAs of a symptom-related vessel, both in total population and in patients with unstable angina, and plaque volume index of the NC of all three vessels were independent factors associated with thick EAT. In multiple linear regression models of VH-IVUS parameters which means plaque vulnerability, EAT thickness was one of the independent factors. In the present study, the VH-IVUS parameters indicating vulnerable plaque were significantly related with the thickness of EAT.