Intramedullary (IM) nailing is currently the most common method for treating patients with impending pathologic humeral fractures; however, this treatment is associated with known complications primarily owing to violation of the rotator cuff during insertion. A better option is needed. To determine if a humeral segmental replacement prosthesis would provide a stronger construct compared with an IM nail in this setting, we compared the mechanical properties of these two devices in a cadaver model simulating an impending pathologic fracture. In each of nine matched pairs of fresh human humeri one was randomly selected to undergo a 50% lateral middiaphyseal defect simulating an impending pathologic fracture and subsequent fixation with an IM nail and bone cement. The contralateral humerus underwent fixation using a humeral segmental defect prosthesis. We determined T-scores using DEXA. Each specimen subsequently was tested in torsion to failure. Peak torque and peak rotation at failure were greater for the prosthesis specimens whereas torsional stiffness was greater for the IM nail specimens. We found a linear relationship between peak torque and T-score for each device with the slopes of the lines suggesting the construct with the prosthesis can withstand greater forces than the IM nail and the differences between devices were greater in weaker bones.