Background <p>Platinum-resistant high-grade serous ovarian cancer (HGSOC) is a fatal disease. The main goal of current study is to develop new strategies to predict platinum resistance, moving towards personalized therapy. Currently, there are no validated biomarkers able to predict at diagnosis platinum resistance. Circulating tumor-derived extracellular vesicles (EVs) represent a liquid biopsy of the tumor of origin and reflect its biological profile. EpCAM-expressing EVs are largely used biomarkers of epithelial cancers in translational research. Aim of this study was to quantify, by nano-flow cytometry, circulating EpCAM+ EVs in patients with histologically confirmed diagnosis of HGSOC FIGO stage III/IV, before and after intravenous administration of the first dose of chemotherapy with paclitaxel and carboplatin, and correlate EVs levels to platinum-sensitivity. As comparison, leukocyte-derived EVs were also assessed using the pan-leukocyte marker CD45.</p> Results <p>Patients with platinum-sensitive HGSOC showed significantly lower pre-chemotherapy circulating levels of both EpCAM+ and CD45+ EVs compared to platinum-resistant cases (<i>p&lt;</i>0.01). Platinum-sensitive patients displayed significantly higher levels of circulating EpCAM+ and CD45+ EVs 21 days post administration of the first dose of chemotherapy compared to pre-treatment levels (<i>p&lt;</i>0.05 and <i>p&lt;</i>0.01, respectively). Platinum-resistant and platinum-refractory patients showed significantly higher EpCAM⁺CD45⁺ EVs levels than platinum-sensitive patients (<i>p&lt;</i>0.01, <i>p&lt;</i>0.05, respectively).</p> Conclusions <p>Tumor-derived EVs are valuable candidate biomarkers for early prediction of platinum resistance and need to be investigated in larger prospective clinical studies.</p>