Clusterin has been reported to play a significant role in tumorigenesis, and its overexpression occurs in various human malignancies. We examine the clusterin overexpression in human hepatocellular carcinoma (HCC) and verify its clinical usefulness as a candidate biomarker by clinicopathologic and survival analysis. We examined clusterin overexpression immunohistochemically in 100 surgically resected HCCs using the tissue microarray method. A total of 89 HCCs exhibited clusterin overexpression, in 2 distinct staining patterns, cytoplasmic (n=35) and canalicular (n=54). Clusterin positivity demonstrated an inverse correlation with tumor cell apoptosis evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay (P=0.024). Within the clusterin-positive group, cytoplasmic overexpression had a positive correlation with tumor cell proliferative activity measured by the Ki-67 labeling index (P=0.003). HCCs demonstrating cytoplasmic clusterin overexpression were associated with poor Edmondson's histological grade and high TNM stage (P <0.05). In the survival analysis, the cytoplasmic-positive group demonstrated an overall poorer prognosis than the canalicular-positive group, according to univariate and multivariate analysis (P <0.05). In HCC, clusterin may play an important role in tumorigenesis and progression, corresponding to its subcellular localization. Cytoplasmic clusterin overexpression could be a potential new prognostic marker for the aggressiveness of HCC.