Background: The prognosis of relapsed and unresectable high-grade osteosarcoma is poor and has remained unchanged for decades. Increased survival for metastatic soft tissue sarcomas was previously shown with the combination G+D compared to G alone (Maki R, JCO 2007). Thus, we explored G+D activity in patients (pts) with relapsed and unresectable osteosarcoma / spindle cell pleomorphic sarcoma. Methods: Pts progressing after standard treatment were eligible to receive G 900 mg/m²day 1, 8 + D 75 mg/m2 day 8, every 21 days, until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months (mo). Secondary objectives were overall survival (OS) and disease control rate (DC), defined as complete response (CR), partial response (PR) or stable disease (SD) lasting at least 6 months. Results: We enrolled 46 pts. Median age was 18 (8-71): 26 pts pediatric pts, 20 adult. Line of treatment: 14 pts in 1^stline; 32 pts were in ≥ 2nd line (up to 5). Pattern of metastases: 26 pts lung only, 20 multiple sites. Histology: 35 pts classic osteosarcoma, 11 high grade spindle cell sarcoma (HGS). ECOG: 31 pts 0, 11 pts 1, 4 pts 2. 41 pts were evaluable for RECIST response (2 pts off study for D allergic reaction, 1 pt for G4 skin toxicity, 2 pts with no measurable lesions). 4-mo PFS rate was 47%. 4-mo PFS was significantly better for ECOG 0 pts (ECOG0: 57% vs ECOG 1: 37% vs ECOG 2: 0%; p= 0.01), with a trend to superiority in pts with lung only metastases (lung only: 58%; multiple sites: 35%; p=0.09), and classic osteosarcoma (classic osteosarcoma 50% vs. HGS 22%; p=0.2), while there was no difference according to age or line of treatment. PFS and OS at 6 mo were 23% and 71%, respectively. Tumor responses: CR: 0/41, PR: 5/41 (12%), SD 18/41 (44%), progressive disease (PD) 18/41 (44%); DC: 8/41 (20%). Conclusions: G+D demonstrated activity in pre-treated relapsed high grade classic osteosarcoma pts, especially in pts with ECOG 0 and lung only disease. This combination should be included in the therapeutic armamentarium of metastatic osteosarcoma as an active line of therapy.