Five-hundred and twenty-six patients with non-metastatic osteosarcoma of the extremities treated at Istituto Ortopedico Rizzoli from 1983 to 1995 with neoadjuvant chemotherapy and limb salvage, were retrospectively studied to evaluate the rate of local and systemic control. At a mean follow-up of 9.5 years (3-17), 320 patients remained continuously free of disease and 206 relapsed. The 5-year disease-free survival and overall survival were 64% and 70% respectively. In patients who relapsed, there were 31 local recurrences (6%). The rate of local failures was significantly higher in the 79 patients with inadequate surgical margins (marginal, intralesional, and contaminated margins) than in the 486 patients with wide surgical margins (2.6% vs. 25.0%; P<0.0001). Twenty-nine of the 31 patients (94%) with local recurrence also had metastases and died of the tumor. In comparison with patients who only had a systemic relapse, patients with local recurrences had a higher rate of metastases located in bones (41% vs. 7%; P<0.001), and a worse post-relapse outcome (5-year overall survival: 6% vs. 24%; P<0.04). We concluded that in osteosarcoma of the extremity treated with neoadjuvant chemotherapy: i) limb salvages procedures do not compromise the outcome of patients, provided the achievement of adequate surgical margins; ii) local recurrences are a marker either of the inadequacy of local treatment or of the high local and systemic aggressiveness of the tumor.