Studies have estimated that 5–10% of all fractures are associated with impaired healing, resulting in delayed union or non-union. Bone defects can result from a high-energy traumatic event, from large bone resection for different pathologies such as tumours or infections or from the treatment of complex non-unions. A large bone defect represents a challenge for the orthopaedic surgeon. This clinical condition is considered critical in relation to the skeletal segment involved: 3 cm for the forearm, 5 cm in the femur and tibia, 6 cm in the humerus. Excluding the traditional surgical techinques (distraction osteogenesis, autologous bone grafts or arthrodesis), the use of biotechnology can be very useful. We treated a 42 years old patient, that came to our observation through the ambulatory of nonunion of our Institute with a diagnosis of “humeral large bone septic defect”; this patient had in his history multiple previous osteosynthesis surgeries. The patient therefore underwent corrective surgery according to the Masquelet’s technique in two surgical times. The postoperative course was uneventful; during the follow-up the patient showed a good functional recovery with great satisfaction.