BackgroundRenal cell carcinoma (RCC) is a prevalent malignancy with a rising incidence in developing countries. Clear cell renal cell carcinoma (ccRCC) constitutes 70% of RCC cases and is prone to metastasis and recurrence, yet lacks a liquid biomarker for surveillance. Extracellular vesicles (EVs) have shown promise as biomarkers in various malignancies. In this study, we investigated the potential of serum EV-derived miRNAs as a biomarker for ccRCC metastasis and recurrence.Materials and methodsPatients diagnosed with ccRCC between 2017 and 2020 were recruited in this study. In the discovery phase, high throughput small RNA sequencing was used to analyze RNA extracted from serum EVs derived from localized ccRCC (LccRCC) and advanced ccRCC (AccRCC). In the validation phase, qPCR was employed for quantitative detection of candidate biomarkers. Migration and invasion assays were performed on ccRCC cell line OSRC2.ResultsSerum EVs derived hsa-miR-320d was significantly up-regulated in patients with AccRCC than in patients with LccRCC (p < 0.01). In addition, Serum EVs derived hsa-miR-320d was also significantly up-regulated in patients who experienced recurrence or metastasis (p < 0.01). Besides, hsa-miR-320d enhances the pro-metastatic phenotype of ccRCC cells in vitro.ConclusionsSerum EVs derived hsa-miR-320d as a liquid biomarker exhibits significant potential for identifying the recurrence or metastasis of ccRCC, as well as hsa-miR-320d promotes ccRCC cells migration and invasion.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-023-00730-2.