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Background and purpose: Approximately 60% of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage, therefore cannot receive timely and effective treatment. At present, the sensitivity of serum biomarkers commonly used in the diagnosis of HCC is low. In this paper, through the differential expression analysis of plasma exosomal proteome, the candidate exosome protein markers which may be used in the diagnosis of HCC were identified. Methods: First, we performed shot-gun proteome mass spectrometry assays in the plasma exosomes from the discovery cohort [including 4 healthy control (HC) group and 4 HCC patients group], and identified differentially expressed proteins by qualitative and quantitative analyses. Then, we carried out enzyme-linked immunosorbent assay (ELISA) in plasma samples of an independent verification cohort [including 56 HCC patients group, 20 liver cirrhosis (LC) patients group and 48 HC group], and evaluated the diagnostic value of the candidate protein in HCC. Results: In the discovery cohort, we identified a total of 1 434 exosomal proteins, of which CD48 exhibited higher levels in HCC than in HC. We further verified in the validation cohort by ELISA that CD48 was markedly higher in HCC compared with LC and HC groups, with the area under receiver operating characteristic (ROC) curve (AUC) of 0.886. When combined with plasma alpha-fetoprotein (AFP), the AUC reached 0.970. Conclusion: The plasma exosomal CD48 protein can be used as a candidate diagnostic biomarker for HCC, and its combination with AFP may further improve the clinical diagnostic ability for HCC.