We developed a new method to measure the voxel-based vessel-wall-plus-plaque volume (VWV). In addition to quantifying local thickness change as in the previously introduced vessel-wall-plus-plaque thickness (VWT) metric, voxel-based VWV further considers the circumferential change associated with vascular remodeling. Three-dimensional ultrasound images were acquired at baseline and 1 y afterward. The vessel wall region was divided into small voxels with the voxel-based VWV change (ΔVVol%) computed by taking the percentage volume difference between corresponding voxels in the baseline and follow-up images. A 3-D carotid atlas was developed to allow visualization of the local thickness and circumferential change patterns in the pomegranate versus the placebo groups. A new patient-based biomarker was obtained by computing the mean ΔVVol% over the entire 3-D map for each patient (ΔVVol%¯). ΔVVol%¯ detected a significant difference between patients randomized to pomegranate juice/extract and placebo groups (p = 0.0002). The number of patients required by ΔVVol%¯ to establish statistical significance was approximately a third of that required by the local VWT biomarker. The increased sensitivity afforded by the proposed biomarker improves the cost-effectiveness of clinical studies evaluating new anti-atherosclerotic treatments.