Background/Aims: To investigate Omi/HtrA2 expression and its clinical significance in hepatocellular carcinoma. Methodology: We analyzed Omi/HtrA2 expression in hepatocellular carcinoma, paracancerous tissues and normal hepatic tissues by immunohistochemistry, RT-PCR and Western blot. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression was also detected in hepatocellular carcinoma samples by immunohistochemistry. Meanwhile, we retrospectively analyzed the relationship between Omi/HtrA2 expression and the survival times of the patients. Results: We found that Omi/HtrA2 over-expressed in hepatocellular carcinoma and was correlated with hepatocellular carcinoma differentiation, tumor size, portal vein invasion, clinical stage and lymph node metastasis. We also observed a significant inverse correlation between the expression of Omi/HtrA2 and HIF-1 alpha in hepatocellular carcinoma. The Kaplan-Meier estimates showed that patients who were Omi/HtrA2 positive had much longer survival times than those who were Omi/HtrA2 negative. Both univariate and multivariate analysis using the Cox regression model indicated that Omi/HtrA2 expression was a significant factor for prognosis. Conclusions: Hepatocellular carcinoma cells may need Omi/HtrA2 expression for apoptosis and Omi/HtrA2 might be an important prognostic marker for primary hepatocellular carcinoma.