Many battlefield injuries involve penetrating soft tissue trauma often accompanied by skeletal muscle defects, known as volumetric muscle loss. This article presents the first known case of a surgical technique involving an innovative tissue engineering approach for the repair of a large volumetric muscle loss. A 19-year-old Marine presented with large volumentric muscle loss of the right thigh as a result of an explosion. The patient reported muscle weakness with right knee extension, secondary to volumentric muscle loss, primarily involving the vastus medialis muscle. This persisted 3 years postinjury, despite extensive physical therapy. With all existing management options exhausted, restoration of a portion of the lost vastus medialis muscle was attempted by surgical implantation of a multi-layered scaffold composed of extracellular matrix derived from porcine intestinal submucossa. The patient had no complications, was discharged home on postoperative day 5, and resumed physical therapy after 4 weeks. Four months postoperatively, the patient demonstrated marked gains in isokinetic performance. Computer tomography indicated new tissue at the implant site. This approach offers a treatment option to a heretofore untreatable injury and will allow us to improve future surgical treatments for volumetric muscle loss.