Endometrial cancer is the most prevalent gynaecological cancer globally. Its association with obesity and metabolic diseases is a key aetiology, increasingly among younger females. Early diagnosis and improved treatment decisions are crucial for these women whose outcomes could be improved by discovering new biomarkers. We took a new approach to extracellular vesicle (EV) biomarker discovery - profiling the proteome of enriched EVs isolated directly from frozen biobanked endometrial cancers. Nine tissue pools, each generating collagenase-digested tissue and matched small EVs, were analysed using label-free proteomics. Three clinical subgroups: Endometrioid low BMI (body mass index), Endometrioid high BMI, and Serous, irrespective of BMI, were compared to identify shared secreted proteins, proteins associated with histological subtype, and proteins related to BMI. EVs were enriched for common EV markers and large secreted proteins. Cell lysates were enriched in mitochondrial and blood proteins. EV protein profiles were most different between the high BMI subgroup and the others, highlighting a significant influence of comorbidities on the intra-tumoural EV secretome. Proteins differentially abundant between subgroups in tissues were strikingly not also differential in the matched EVs. This work has identified secreted proteins implicated in the complex pathophysiology of endometrial cancer and pinpointed candidate biomarkers for diagnosis.