Twenty pathologic fractures occurred in 285 patients with soft tissue tumors that were treated with radiation therapy and surgery. Twelve of these fractures occurred in 11 patients from a subpopulation of 163 patients with 168 soft tissue tumors of the thigh (155 soft tissue sarcomas and 13 aggressive fibromatosis). The fractures occurred at a mean of 40.5 months after treatment and were not associated with significant trauma. Risk factors associated with the development of fracture included tumor location within the anterior compartment of the thigh, extensive surgical periosteal stripping, and a marginal or intralesional margin of resection. The dose, timing, and fractionation of radiation therapy were not related to the risk of fracture. A high rate of complications was seen with this series, including fracture nonunion (45%) and deep infection (20%). Prophylactic intramedullary fixation of the femur should be considered for patients undergoing resection of large tumors in the anterior compartment of the thigh requiring extensive periosteal stripping and adjuvant radiation therapy.