This study analyzed 22 unique OS patient-derived xenografts (PDXs) using proteomics to identify surface proteins for potential immunotherapeutic targeting. Plasma membranes were enriched using density gradient ultracentrifugation and compared to a reference standard of 12 immortalized non-OS cell lines prepared in a similar manner. In parallel, global proteome analysis was carried out on all samples to place the identified surface proteins within the context of deregulated OS pathways. All models were analyzed by Tandem Mass Tags (TMT)-based mass spectrometry to quantify identified proteins.