Treatment of small ( 2cm) HCC tumours can be achieved by surgical resection and complete eradication always correlates with good patient's outcome, with low local recurrence and high survival rates. Indeed, surveillance program for the early detection of small HCC tumour is imperative to facilitate curative treatment, and hence better survival. Discovery of new blood-based biomarkers is obligatory and vimentin is a distinct novel small HCC tumour marker herein identified using proteomics. Experimental design: A total of 76 liver tissues were evaluated by 2-DE analysis. Differentially expressed proteins were unequivocally identified by MALDI-TOF/TOF and validation of the best candidate from protein to gene levels. Indirect ELISA assay was developed to detect soluble vimentin from 152 serum samples. Results: Vimentin was significantly over-expressed in small HCC tumours compared to non-malignant controls and maintained expression in >2cm tumours using 2-DE analysis. Blind verification displayed over-expression of vimentin in both transcripts and proteins levels. Soluble vimentin was significantly detected at high level in small HCC as well as in overt HCC tumours. Receiver operating characteristic analysis showed vimentin exhibited 40.91% sensitivity and 87.50% specificity in detecting small HCC at a cutoff of 245ng/ml. Combined diagnostic performance of soluble vimentin and serum AFP increases the detection sensitivity and specificity to 50.53% and 98.15%, respectively. Conclusion: In this context, over-expression of vimentin is associated with the favourable 2cm sub-class of HCC thus may potentially be used as an effective serum-based diagnostic marker for cancer surveillance in high-risk cirrhotic patients.