Background: The effectiveness of eribulin and irinotecan in treatment of xenograft models of Ewing sarcoma is well-established but no clinical data has been reported. Methods: The medical records of patients treated for refractory or recurrent Ewing sarcoma with 1.4mg/m 2 D 1,8 eribulin and 20mg/m 2/d D 1-5,8-12 irinotecan at 21 day intervals (ERII) at Peking University People’s Hospital (PKUPH) were retrospectively reviewed. Results: A total of 17 patients with median age 18.6 years were treated with a total of 77 courses of ERII between February 2022 and February 2023. The objective response rate was 35.3%, disease control rate 58.9% and the median event-free survival (EFS) 2.07 months. 35.3% patients had 6 months EFS and overall survival was 66.9%. Grade 3 or 4 toxicities were observed in 37.6% courses and in 64.7% of the patients, with myelosuppression, especially neutropenia, being the most common and diarrhea / abdominal pain the second most common. Conclusions: The combination of eribulin and irinotecan as a second-line regimen is well-tolerated and shows promising efficacy. There is scope for further research into the synergistic mechanism of the two agents and into potential biomarkers.