We tested Ewing sarcoma tumors for microsatellite instability (MSI) and loss of heterozygosity (LOH) to investigate the role of genomic instability (GI) in this sarcoma. We detected a high frequency of GI (57%), mostly on 1p and 11p, 35% and 30%, respectively. Patients with GI compared to those with stable genome had a median progression-free survival (PFS) and overall survival (OS) of 24 months and 70 months, compared with 39 and 84 months, respectively. MSI was observed in 48% (11/23) of the tumor samples. Low-MSI (L-MSI) patients (with MSI presented at only one locus) tended to have a better prognosis, 70% PFS, compared with 25% in the high-MSI (H-MSI) group (P=0.13). LOH without MSI did not correlate with progression. H-GI (MSI and/or LOH in > or =30% of tested markers) tended to associate with an adverse prognosis (P=0.28), and correlated significantly with the pelvic site of the primary tumor (P=0.02). The instability of 1p was not associated with progression, while alterations at the 11p locus tended to correlate with a more aggressive disease (P=0.18). Our data suggest that GI may play a role in Ewing sarcoma clinical behavior and outcome.