The tumor-suppressor ING3 has been shown to be involved in tumor transcriptional regulation, apoptosis and the cell cycle. Some studies have demonstrated that ING3 is dysregulated in several types of cancers. However, the expression and function of ING3 in human hepatocellular carcinoma (HCC) remains unclear. The aim of this study is to investigate ING3 expression in hepatic tumors and its clinical relevance in hepatic cancer. The expression of ING3 protein was examined in 120 dissected HCC tissues and 47 liver tissues adjacent to the tumor by immunohistochemical assays and confirmed by Western blot analysis in 20 paired frozen tumor and non-tumor liver tissues. The relationship between ING3 staining and clinico-pathological characteristics of HCC was further analyzed. The mRNA expression of ING3 in the dissected tissues was also analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and realtime PCR. Both mRNA and protein concentrations of ING3 were found to be downregulated in the majority of HCC tumors in comparison with matched non-tumor hepatic tissues. Analysis of the relationship between ING3 staining and clinico-pathological characteristics of HCC showed that the low expression of ING3 protein is correlated with more aggressive behavior of the tumor. Kaplan-Meier curves demonstrated that patients with a low expression of ING3 have a significantly increased risk of shortened survival time. In addition, multivariate analysis suggested that the level of ING3 expression may be an independent prognostic factor. Our findings indicate that ING3 may be an important marker for human hepatocellular carcinoma progression and prognosis, as well as a potential therapeutic target.