The treatment and outcome of two patients suffering from osteosarcoma of the lower extremity evolving many years after manifestation of chronic osteomyelitis are reported. After neoadjuvant polychemotherapy in one patient en bloc resection, interposition of a cement spacer and stabilization was performed in both cases. After eradication of infections final segmental reconstruction was accomplished by knee arthrodesis using rotation plasty of the split femoral condyle, free local fibula transposition and gastrocnemius muscle transfer. A custom-made diaphyseal replacement (3D-rapid prototyping titanium mesh) was used for defect reconstruction. After 1 year postoperative follow-up and restaging both patients showed no evidence of recurrent disease and had no local or systemic signs of infection.