More than 80% of hepatocellular carcinoma (HCC) arises in HBV based liver cirrhotic patients, suggesting that patients with cirrhosis form the main risk group of HCC. α fetoprotein (AFP) has poor sensitivity for the detection of AFP-negative and/or small tumors in HCC patients. Screening serum markers, along with HCC surveillance in patients with cirrhosis, can lead to the detection of HCC at an earlier stage, when curative therapy is likely to be more successful. Sera from 27 patients with HCC and 10 patients with HBV based liver cirrhosis (LC) were screened by comparative proteome analysis. Five significantly differential proteins (HP, Hp2, preprohaptoglobin, SP40 and SAA1) were identified using 2DE followed by MALDI-TOF-MS analysis. Haptoglobin (HP) was identified and found to be overexpressed in HCC as compared with LC. The result from Western blot analysis and turbidimetry detection showed serum levels of HP in HCC patients were significantly (p<0.05) higher than those in LC patients, which was consistent with the result of 2-DE. In addition, combining HP and AFP greatly improved the diagnostic accuracy (AUC=0.838). Additionally, serum HP also showed potential diagnostic value (AUC=0.763) for AFP-negative HCC patients. Altogether, it suggested that serum HP as a candidate marker complementary to α fetoprotein.