Breast cancer screening is beneficial when it averts progression of disease to metastasis, but adverse effects to patients and unnecessary medical expense may result downstream from false positives. Achieving early breast cancer detection with high sensitivity and specificity remains a challenge that may be met by using acoustic radiation force to assess the mechanical properties of tissue. The objective of this study is to evaluate in vivo the diagnostic relevance of Viscoelastic Response (VisR)-derived metrics for mechanical anisotropy. We compare our in vivo human results against biopsy findings. This study analyzed 9 breast lesions (4 malignant, 5 benign) imaged in vivo in women with BIRADS-4 or -5 ratings after standard screening. VisR relative elasticity (RE), relative viscosity (RV), and peak displacement (PD) were measured for each transducer orientation, and fit to a sinusoid by least-squares minimization, extrapolating to 360°. The fits were phase-aligned, and the point-wise differences in each parameter between lesion and background were integrated over angle. Finally, the ratio of the maximum to the minimum parameter value was calculated to reflect the degree of anisotropy (DoA). DoAs by PD, RE, and RV were statistically significantly greater in background than in lesion for all malignant cases but statistically significantly smaller in background than in lesion for all benign cases (Wilcoxon, p < 0.05). Additionally, differences between lesion and background integrated over angle by RE, RV and PD were statistically significantly different (Wilcoxon, p < 0.05) for malignant and benign lesions across all examined patients. These results suggest that VisR-derived mechanical anisotropy assessment could be diagnostically relevant for discriminating malignant from benign breast lesions.