Chemotherapy has long been suspected of having an adverse effect on bone healing. Massive tumor endoprostheses which achieve osseointegration via compressive force provide a unique model to study the effects of chemotherapy on bone healing. We compared distal femoral bone hypertrophy in patients who received chemotherapy with those who did not. Fifty four patients underwent distal femoral reconstruction with a compression implant. Thirty patients received chemotherapy (Group 1), and 24 did not (Group 2). The group of patients receiving chemotherapy was younger, had lower body mass indices, and had different diagnoses compared to the group of patients not receiving chemotherapy. We used a standardized technique to measure bone growth at the bone-prosthetic interface. The rate of cortical width increase at the bone-prosthetic junction was faster in Group 2 compared to Group 1. Similarly, the increase in cortical width from immediate postop to 3 months and 6 months postop was greater in Group 2 when compared to Group 1. The data suggest chemotherapy administration for musculoskeletal malignancy has a substantial initial adverse effect on bone hypertrophy and a trend towards reduced prosthetic survival. These findings have important implications for the patients with musculoskeletal tumors.