Abstract More than 300,000 new cases of head and neck cancer occur each year around the world, and although it is not one of the most common tumors in the world, has an elevated morbidity rate (37.8%) after five years of diagnosis. The development and progression of the Oral Squamous Cell Carcinoma (OSCC) involve complex cellular mechanisms which contribute to a tumor progression. Recently extracellular vesicles (EVs) have taken a significant physiological and pathological role in cell-cell communication through interactions mediated by receptors or by transfer of bioactive molecules such as receptors, proteins, lipids, mRNA, microRNA, and DNA, by changing the phenotype of the recipient cell. The tumor cells can transfer information to different cell types using EVs as a vehicle, modifying the characteristics of the tumor microenvironment, and contributing to cancer sustaining. The detection of alterations in the EVs proteome may, therefore, contribute to the understanding the cellular mechanisms modulated in OSCC and help to improve the clinical prognosis and potential therapeutic targets in oral cancer. Thus, this study analyzed the cargo proteins of different EVs from less and high aggressive oral cancer cells to understand their possible role in microenvironment modulation and oral cancer progression. Our results indicate that EVs of aggressive cells have exclusive proteins that may contribute to lymph node metastasis, which is the worse prognostic factor in OSCC and can be considered potential targets in OSCC.FAPESP: 2016/19337-3 Citation Format: Ana K. Oliveira, Ariane F. Busso-Lopes, Jamile Oliveira Sá, César Rivera, Adriana F. Paes Leme. Proteomics analysis of oral cancer cell-derived extracellular vesicles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5648.