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Soft tissue sarcomas (STSs) represent 1% and 15% of adult and pediatric tumors, respectively, and almost 75% of all sarcomas; primary STSs occur commonly in the lower extremities. Leiomyosarcomas originate from the malignant transformation of a smooth muscle cell, which in turn may arise from a pluripotent mesenchymal stem cell. The present case report describes a patient with a leiomyosarcoma arising from the posterior thigh musculature, which invaded all layers of the left sciatic nerve's tibial division. Only two similar case reports exist in the literature, documenting sciatic nerve involvement by a leiomyosarcoma. The current patient underwent preoperative fractionated external beam radiation therapy (FEBRT) to the tumor and then had its removal which resulted in a 12 cm resection of the tibial division of the sciatic nerve. This defect was repaired with an intrafascicular sural nerve graft. Postoperatively, she had weakness of left hip flexion, dorsi- greater than plantar flexion, and left eversion, all of which reverted to normal after approximately two years. After surgery, the patient received further FEBRT, developed pulmonary involvement by leiomyosarcoma and underwent bilateral thoracotomies with removal of all nodules. She underwent chemotherapy (CTX) with ifosfamide and doxorubicine, the latter switched to epirubicin, but developed a new pulmonary nodule five months after CTX completion. Other CTX trials were unsuccessful, and she succumbed five years after her original extremity tumor complete resection.