Ewing sarcoma (EwS) is the second most common bone sarcoma in children, with 1 case per 1.5 million in the United States. While the survival rate of patients diagnosed with localized disease is ~70%, this decreases to ~30% for patients with metastatic disease and only ~10% for treatment refractory disease, which remain unchanged for decades. Clearly, new therapeutic strategies are urgently needed for metastatic/refractory EwS. In this study, 19 unique EwS patient or cell line-derived xenografts were analyzed using proteomics to identify surface proteins with potential for immunotherapeutic targeting. Plasma membranes were enriched from each model via density gradient ultracentrifugation and compared to a reference standard consisting of 12 immortalized non-EwS cell lines prepared in a similar manner. In parallel, global proteome analysis was carried out on each model and reference controls to compliment the surfaceome data. All models were analyzed by Tandem Mass Tags (TMT)-based mass spectrometry to quantify identified proteins.