Segment skeletal defects that result from resection of a malignant bone neoplasm commonly are reconstructed with large segment allografts. Excellent functional results after these reconstructions and significant complications have been reported. Although it is known that a common complication seen with the use of allografts is allograft fracture, the factors associated with allograft fracture are not entirely clear. In this study, the hypothesis was examined that allograft reconstructions, which use internal fixation devices that penetrate the cortex of the allograft, are associated with an increased risk of fracture. Findings from large segment allograft reconstructions in 74 patients with a minimum followup of 36 months were studied. These 74 patients include 35 patients whose outcomes were reported previously and now have additional followup and 39 patients whose outcomes are being reported for the first time. Thirty-one of the 74 (42%) allografts fractured, and the mean time to fracture was 26 months. When the fixation techniques resulted in cortical penetration of the allograft, fractures occurred in 27 of the 43 (63%) allografts, and when fixation of the graft to the host bone required no cortical penetration, only four of the 31 (13%) allografts fractured. Fractures occurred in 12 of 15 (80%) tibial allografts and in only two of 17 (12%) proximal femoral allografts; however, the anatomic site was not statistically independent of method of fixation because 14 of the 15 tibial grafts had cortical penetration and 15 of the 17 proximal femoral grafts had no cortical penetration. The authors' analysis indicates that internal fixation devices that require cortical penetration are associated with an increased risk of allograft fracture.