Helical plates used for proximal humeral shaft fracture fixation avoid the radial nerve distally as compared to straight plates. To investigate in a human cadaveric model the biomechanical competence of straight lateral plates versus 45° helical plates used for fixation of proximal comminuted humeral shaft fractures, eight pairs of human cadaveric humeri were instrumented using either a long straight PHILOS plate (Group 1) or a 45° helical plate (Group 2) for treatment of an unstable proximal humeral shaft fracture. All specimens were tested under non-destructive quasi-static loading in axial compression, internal and external rotation, and bending in four directions. Subsequently, progressively increasing cyclic loading in internal rotation was applied until failure and interfragmentary movements were monitored by motion tracking. Axial displacement (mm) was 3.13 ± 0.31 in Group 1 and 2.60 ± 0.42 in Group 2, p = 0.015. Flexion/extension deformation (°) in Group 1 and Group 2 was 0.56 ± 0.42 and 0.43 ± 0.23, p = 0.551. Varus/valgus deformation (°) was 6.39 ± 0.44 in Group 1 and 5.13 ± 0.87 in Group 2, p = 0.012. Shear (mm) and torsional (°) displacement were 5.36 ± 0.76 and 17.75 ± 1.06 in Group 1, and 5.03 ± 0.46 and 16.79 ± 1.36 in Group 2, p ≥ 0.090. Cycles to catastrophic failure were 10000 ± 1401 in Group 1 and 9082 ± 1933 in Group 2, p = 0.708. From a biomechanical perspective, 45° helical plating is associated with lower axial and varus/valgus displacement under axial loading and demonstrates comparable resistance to failure versus straight plating. Therefore, 45° helical plates can be considered as a valid alternative to straight plates for treatment of proximal humeral shaft fractures.