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Aim Chronic rejection (bronchiolitis obliterans syndrome (BOS)) is the major limitation for long-term survival after lung transplantation (LTx). Its pathogenesis, however, is poorly understood and no effective predictive biomarkers have been identified. Several studies have shown that de novo development of antibodies to donor mismatched HLA (DSA) is a significant risk factor for the development of BOS. Methods Thirty LTx recipients from Barnes Jewish Hospital/Washington University School of Medicine (10 stable DSA− and BOS−, 10 DSA+ BOS− and 10 DSA+ and BOS+) were analyzed for circulating microRNAs (miRNAs). MiRNAs expression in the recipients’ serum was detected using RNA extraction and quantitative PCR analysis. Results We identified eight miRNAs which were selectively expressed on lung allograft recipients with de novo developed DSA and diagnosed with BOS in comparison to stable LTx without DSA and BOS: miR-369-5p, miR-144, miR-134, miR-10a, miR-195 miR-142-5p, miR-133b, and miR-155 ( p < 0.01). Among them, transforming growth factor beta (TGF- β ) associated miRNAs: miR-369-5p was down regulated (2.3-fold, p < 0.001), miR-144 was up-regulated (3.1-fold, p < 0.001) in the serum of LTx with DSA compared to stable, indicating their role in fibrogenesis mediated by TGF- β signalling. In addition, miR-134 involved in B cell receptor pathway was decreased ( p < 0.001) in the serum of LTx with DSA and BOS, demonstrating its role in B cell activation and DSA development following LTx. Furthermore, miR-10a, known to be associated with Treg development, was down-regulated ( p < 0.001) in LTx with DSA and BOS, demonstrating its involvement in down regulation of Treg function leading to development of DSA. Finally, results obtained from independent validation using an independent cohort of 9 stable, 7 DSA+ BOS−, and 10 DSA+ BOS+ LTx demonstrated that these miRNAs can discriminate LTx with development of DSA and BOS from those stable LTx without DSA and BOS ( p < 0.01). Conclusion Our results, for the first time, demonstrated differential expression of circulating miRNAs in lung allograft recipients with de novo development of DSA and BOS. These dysregulated miRNAs are involved in T and B cell regulation and fibrogenesis, indicating their role in the development of DSA leading to chronic lung allograft rejection. [ABSTRACT FROM AUTHOR]