Background: Preclinical models show that a daily antiangiogenic regimen at low-dose may be effective against chemotherapy-resistant tumors. In patients (pts) with high grade, operable osteosarcoma (OST) of the extremities, efficacy of maintenance therapy with continuous oral cyclophosphamide and methotrexate was investigated. Methods: Pts ≤30yrs with high-grade OST were eligible for registration at diagnosis. Eligibility for randomization included: 1. Non-metastatic pts 2. high-grade extremity OST 3. receipt of two cycles pre-operative methotrexate, doxorubicin, cisplatin (MAP); 4. complete macroscopic resection of primary tumor. The study design includes a backbone of 10 weeks of preoperative therapy using MAP. Following surgery, non-metastatic pts were randomized by blocks to complete 31 weeks of MAP or to receive 73 weeks of maintenance therapy following MAP; while metastatic pts received maintenance therapy in combination with MAP since the beginning of treatment. The primary end point was event-free survival (EFS) from randomization. Results: Of the 682 pts registered (April, 06 to July, 13) from 3 countries (27 sites), 535 were evaluable, mean age at enrollment of 13.5 years, mean time to diagnosis of 3.8 months and metastatic disease in 38% of the pts. The multivariate analysis showed that metastases at diagnosis (p<0.001), necrosis grades 1 and 2 (p=0.001) and amputation (p=0.02) were associated with a shorter EFS. In the whole cohort of pts, overall survival (OS) was 62% at 5 years and event free survival (EFS) was 50%. For non-metastatic pts, OS was 72% and EFS was 60%. There was no significant difference in EFSbetween pts who received MAP+maintenance chemotherapy comparedwith MAP alone (61% vs 64%, log-rank test p=0.3). Conclusions: OST survival rates were improved by the use of this regimen compared with previously reported results by the group. However, with current follow-up, EFS for MAP+maintenance chemotherapy is not statistically superior to MAP alone in pts with high-grade resectable OST of the extremities. Further follow-up for events and survival continues.