Objective: The cardinal features of asthma include airway inflammation, airway hyper responsiveness (AHR) and airway remodeling. Exosomes help orchestrate the immune response and contain microRNAs (miRNAs) such as miRNA-155 and miRNA-221 which play significant roles in severe asthma pathogenesis and exacerbations. In this study we aimed to investigate the exosomal expression miRNAs (155, 221) in the serum of severe asthma patients. Methods: Eighteen moderate-severe asthma patients and eighteen healthy subjects were recruited to this study. Serum exosomes were isolated and characterized according to their shape, size, and exosomal markers by transmission electron microscopy, dynamic light scattering (DLS) and flow cytometry, respectively. Exosomal miRNA extraction and quantitative real-time PCR (qRT-PCR) was used to measure miR-155 and miR-221. Results: Round exosomes with a mean size of 25.8nm were isolated from serum of asthmatic patients. Flow cytometry shows high expression of CD63 and CD81 on isolated exosomes. Serum exosomes from severe asthma patients and healthy donors contain miR-155 and miR-221 but miR-155 (P?0.0001) and miR-221 expression were significantly increased in severe asthma patients. There was a positive correlation between miR-221 expression and FVC (r= 0.47, p?0.04). Receiver operating characteristic (ROC) analysis indicated that miR-155 and miR-221 had an excellent diagnostic efficiency for predicting asthma Conclusion: Serum exosomal miR-155 and miR-221 may be a biomarker for severe asthma. The results need to be extended in another cohort and further studies with large samples size should be conducted on the effect of these miRNAs on effector cells.