Background <p>The circRNA-miRNA-mRNA networks of extracellular vesicles (EVs) in first-onset schizophrenia (FOS) have not been reported yet. Here, we constructed circRNA-miRNA-mRNA networks of EVs, and examined their diagnostic efficiency in FOS.</p> Methods <p>The expression levels of circRNAs, miRNAs and mRNAs in EVs derived from 10 FOS patients and 10 healthy controls (HC) were determined by high-throughput sequencing. The circRNA-miRNA-mRNA networks was constructed based on the overlapped miRNAs between differentially expressed (DE) miRNAs and circRNA-targted miRNAs, and overlapped mRNAs between DE-mRNAs and miRNA-targeted mRNAs. Gene expression levels were validated using quantitative real-time PCR in 31 FOS and 31 HC cases. Receiver operating characteristic (ROC) curve analysis was performed to examine the diagnostic efficacy. Correlation analysis was performed using Pearson’s or Spearman’s correlation coefficient.</p> Results <p>There were 26,194 DE-circRNAs, 22 DE-miRNAs, and 2637 DE-mRNAs in plasma EVs of FOS patients. Then, the circRNA-miRNA-mRNA networks consisting of 9 circRNA, 6 miRNA and 16 mRNA, were constructed. Three network (chr15:93496587–93499879+—hsa-miR-20b-5p—ANKH; chr7:40037093–40087476+—hsa-miR-22-3p—C5orf24; and chr19:17883266–17883550+—hsa-miR-502-3p—B4GALT5) were selected for further investigation. The expression levels of 9 genes in validation data were consistent with the results of the high-throughput sequencing. The area under the ROC curve (AUC) of the circRNA-miRNA-mRNA network was higher than that of circRNA, miRNA or mRNA alone in plasma EVs, and the AUC of mRNAs in plasma EVs was higher than that of mRNAs in peripheral blood. The expression levels of chr15:93496587–93,499,879+, chr7:40037093–40,087,476+, hsa-miR-22-3p and B4GALT5 were correlated with the PANSS score.</p> Conclusion <p>We constructed the circRNA-miRNA-mRNA networks of plasma EVs in FOS, demonstrating their potential as a biomarker for FOS.</p>