Introduction: Vulnerable plaque is marked by increased intra-plaque vascularity, hemorrhage and is associated with cerebrovascular (CV) events. Current use of 2D CEUS carotid imaging does not provide a true volumetric representation of the intra-plaque angiogenesis. Therefore, this is the first clinical trial using 3D CEUS to assess intra-plaque angiogenesis, in patients with clinically significant plaques prior to carotid endarterectomy (CEA). Methods: Data were acquired on 11 patients that were asked to participate in this pilot study prior to CEA. All patients had MR and/or CT angiogram as part of their standard care and all carotid artery plaque specimens were collected and sent for histologic evaluation. CEUS volumes were acquired using a GE LOGIQ E9, RSP6-16 4D probe and Optison. In order to assess plaque vulnerability, semi-automatic image analysis algorithms were developed to segment the lumen, plaque, and intra-plaque vascularity. Measurements derived from 3D CEUS images were validated against CT...