Objective <p>To understand regional biomechanical differences within the healthy and aneurysmal ascending aorta.</p> Methods <p>Aortic tissue was collected from the inner (IC) and outer (OC) curvature of aneurysms excised during elective surgery (<i>n</i> = 102) and normal aortas from organ donors (<i>n</i> = 25). Biaxial tensile testing and peel testing were performed to derive a comprehensive set of biomechanical parameters.</p> Results <p>In normal aortas, the OC exhibited greater energy loss, lower tangent modulus at low strain, and lower transition zone stress compared to the IC. In aneurysmal aortas, similar findings were observed. All IC and OC biomechanical parameters were linearly correlated in aneurysmal aortas, including delamination strength. Healthy and aneurysmal aortas exhibited similar degrees of difference between IC and OC for most biomechanical properties. Aneurysms with greater biomechanical differences between IC and OC trended toward being older (<i>p</i> = 0.096) with larger diameters (<i>p</i> = 0.051) compared to other aneurysms. Asymmetric bulging exhibited lower stiffness and transition zone stress in the OC, but no difference in delamination strength between regions.</p> Conclusions <p>Regional biomechanical differences exist in aneurysms of the ascending aorta to a similar extent as in healthy aortas. In aneurysms, biomechanical properties of the IC and OC regions were strongly linearly correlated, suggesting that the regional differences in ascending aortic biomechanics are less important than the large biomechanical variability that exists between patients.</p>