Background: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown etiology often leading to respiratory failure. Over half of IPF patients present with discordant features of usual interstitial pneumonia on high-resolution computed tomography at diagnosis which warrants surgical lung biopsy to exclude the possibility of other interstitial lung diseases (ILDs). Therefore, there is a need for non-invasive biomarkers for expediting the differential diagnosis of IPF. Methods: Using mass spectrometry, we performed proteomic analysis of plasma extracellular vesicles (EVs) in a cohort of subjects with IPF, chronic hypersensitivity pneumonitis, nonspecific interstitial pneumonitis, and healthy subjects (HS). A five-protein signature was identified by lasso regression and was validated in an independent cohort using ELISA. We evaluated the concordance between plasma EV proteome and the lung transcriptome data. Lastly, we compared the molecular pathways overrepresented in IPF by differentially expressed proteins and transcripts from EVs and lung tissues, respectively. Results: The five-protein signature derived from mass spectrometry data showed area under the receiver operating characteristic curve of 0.915 (95%CI: 0.819-1.011) and 0.958 (95%CI: 0.882-1.034) for differentiating IPF from other ILDs and from HS, respectively. We also found that the EV protein expression profiles mirrored their corresponding mRNA expressions in IPF lungs. Further, we observed an overlap in the EV proteome- and lung mRNA-associated molecular pathways. Conclusions: We discovered a plasma EV-based protein signature for differential diagnosis of IPF and validated this signature in an independent cohort. The signature needs to be tested in large prospective cohorts to establish its clinical utility.