The ability to visualize breast lesion vascularity and quantify the vascular heterogeneity using contrast-enhanced 3-D nonlinear ultrasound imaging was investigated in a clinical population. Patients (n = 236) identified with breast lesions on mammography were scanned using power Doppler imaging, contrast-enhanced 3D HI, and 3D SHI on a modified Logiq 9 scanner (GE Healthcare). Time-intensity curve volumes were developed corresponding to ultrasound contrast agent flow in the lesions after being identified in 4D View (GE Medical Systems). Time points corresponding to, wash-in, baseline, peak intensity, and washout of ultrasound contrast agent were identified and used to generate and compare vascular heterogeneity plots for malignant and benign lesions. Vascularity was observed with power Doppler imaging in 93 lesions (69 benign and 24 malignant). The 3D HI showed flow in 8 lesions (5 benign and 3 malignant), whereas 3D SHI visualized flow in 83 lesions (58 benign and 25 malignant). Analysis of vascular heterogeneity in the 3D SHI volumes found benign lesions having a significant difference in vascularity between central and peripheral sections (1.8 ± 0.16 vs. 1.2 ± 0.09 dB, p = 0.0003, respectively), whereas malignant lesions showed no difference (1.7 ± 0.33 vs. 1.3 ± 0.21 dB, p = 0.23), indicative of more vascular coverage. Parametric volumes, that contained a single parametric value for every voxel within the 3D volume in order to visualize localized variations, were generated based on perfusion (PER) and area under the curve (AUC). These maps highlighted the variations in the vascularity for individual voxels in the lesion volume. Finally, a preliminary measure for lesion characterization, based on vascular heterogeneity, achieved an area under the ROC of 0.72. These preliminary results suggest quantitative evaluation of vascular heterogeneity in breast lesions using contrast-enhanced 3D SHI is feasible and able to detect variations in vascularity between central and peripheral sections for benign and malignant lesions to aid in characterization.