Between January 1990 and December 2006, 123 patients S 16 years with the histopathologic diagnosis of osteosarcoma were treated with a chemotherapy regimen comprising epirubicin, cisplatin, and ifosfamide. The mean follow-up time was 36 months (range 2-219 months). Among the 94 patients analyzed, 68 patients (72.3%) were alive at the time of the analysis. A total of 26 patients (13 each with nonmetastatic and metastatic disease) died; 20 of these (9 with nonmetastatic disease and 1 1 with metastatic disease) died of disease; 5, of chemotherapy toxicity, and I, of nonmetastatic disease from acute nonlymphoid leukemia 13 months following the cessation of osteosarcoma therapy. The estimated 5- and 10-year Overall Survival (OS) rates for call patients were 64.7% (95% confidence interval [95% CI] 74.8-52.94%) and 62.2% (95% CI 74.6-49.9%), respectively. The Event Free Survival (EFS) rate for all patients was 51.8% (95% CI 40.2-63.4%) at both 5 and 10 years. The estimated 5- and 10-year Overall Survival (OS) rates for patients with nonmetastatic disease were 78.3% (95% CI 66.9-89.7%) and 75.1 (95% CI 62.6-87.6%), respectively; this 5-year rate was significantly superior to that of patients with metastatic disease, 13.5% (95% CI 0-30.8%) (p < 0.001). The estimated EFS rate for patients with nonmetastatic disease was 62.4% (95% CI 49.9-79.9%) at both 5 and 10 years and was significantly better than the 5-year EFS of 6.9% (95% CI 0-19.9%) in patients with metastatic disease (p < 0.001). Progression during pre-operative chemotherapy was encountered in 18 patients (19.1%), 11 of whom had metastatic disease at diagnosis. Four patients (three with nonmetastatic disease and one with metastatic disease) underwent salvage treatment consisting of early Surgical intervention and preoperative radiation. The estimated 5- and 10-year OS rates were 13% (95% CI 0-29.7%) for patients who had progression during treatment; this rate was significantly inferior to both the 5- and 10-year OS rates for patients without progressive disease, which were 78.2% (95% CI 66.1-90.4%) and 75% (95% CI 61.9-83.1%), respectively (p < 0.001). A total of 33 patients experienced relapse and/or progression at a median time of 9 months (range 0-40 months). Histologic response (<90% necrosis vs. >= 90%) was significantly correlated with the 5-year EFS (31% vs. 67.6%, respectively, p=0.023) but not with OS (57.7% vs. 76.5%, respectively, p=0.13). The presence of metastases at diagnosis was found to be the most significant single characteristic influencing the outcome. The rate of histologically good response to preoperative chemotherapy was 64.5%, which is comparable with the 28-85% response rates given in the literature. Our results demonstrate that the combination of epirubicin, cisplatin, and ifosfamide is an active and reasonably well-tolerated regimen for childhood osteosarcoma.