To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.