BACKGROUND Patients with metastatic, progressive or recurrent Ewing sarcoma (ES) have a dismal outcome. The combination of irinotecan and temozolomide has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination with vincristine for patients with relapsed and refractory ES. MATERIALS AND METHODS Twenty-two patients with relapsed or refractory ES were treated with the combination of vincristine (1.5 mg/m(2) i.v. day 1), irinotecan (50 mg/m(2) /day i.v. days 1-5) and temozolomide (125 mg/m(2) /day p.o. days 1-5) (VIT) during the period 2008-2012. All toxicities were documented. RESULTS A total of 91 cycles (median 4.1 cycles/patient) were administered. A complete response (CR) was achieved in five patients, partial response (PR) in seven patients, stable disease (SD) in three patients, and progression disease (PD) in seven patients, with an overall response rate of 68.1%. Median time to progression was 3.0 months (range 1.1-37.1 months). Five patients (22.7%) are alive with no evidence of disease with a median follow-up of 10.3 months (range 2.1-46.5); four of them received consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplant after responding to VIT. Outcome was better for patients with relapsed ES compared with patients who progressed to initial therapy (estimated 2 year overall survival 36.4% vs. 0%, respectively). There were no significant toxicities. CONCLUSIONS The shorter, 5-day VIT regimen is an active and well-tolerated regimen in refractory ES. This combination deserves further investigation in the upfront management of patients with metastatic disease.