The poor prognosis of patients with hepatocellular carcinoma (HCC) is attributed to intrahepatic recurrence. To understand the molecular background of early intrahepatic recurrence, we conducted a global protein expression study. We compared the protein expression profiles of the primary HCC tissues of 12 patients who showed intrahepatic recurrence within 6 months post surgery with those of 15 patients who had no recurrence 2 years post surgery. Two-dimensional difference gel electrophoresis identified 23 protein spots, the intensity of which was highly associated with early intrahepatic recurrence. To validate the prediction performance of the identified proteins, we examined additional HCC tissues from 13 HCC patients; six with early intrahepatic recurrence and seven without recurrence. We found that all but one of the 13 patients were grouped according to their recurrence status based on the intensity of the 23 protein spots. Mass spectrometry identified 23 proteins corresponding to the spots. Although 13 of 23 have been previously reported to be correlated with HCC, their association with early intrahepatic recurrence had not been established. The identified proteins are involved in signal transduction pathways, glucose metabolism, cytoskeletal structure, cell adhesion, or function as antioxidants and chaperones. The identified proteins may be candidates for prognostic markers and contribute to the improvement of existing therapeutic strategies.