This study consisted of 2 aims: (i) to determine genes associated with hepatocellular carcinoma (HCC) by microarray analysis; and (ii) to evaluate the clinicopathological significance of human ubiquitin-conjugating enzyme E2C (Ube2c) found to be overexpressed in HCC from microarray analysis. Laser microdissection and cDNA-microarray were performed to identify genes associated with HCC. We then focused on the Ube2c gene. Using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR), Ube2c expression status and clinicopathological significance were studied in 65 clinical HCC samples. A number of genes upregulated in HCC cells compared to noncancerous liver cells were identified, one of which was the Ube2c gene. Ube2c gene expression in the cancer tissue was higher than in the corresponding noncancerous tissue in 62 of the 65 cases (95.4%, p < 0.01). Tumors with high Ube2c expression showed higher frequencies of tumor invasion to capsular formation (fc-inf), invasion to portal vein (vp) and tumor de-differentiation (p < 0.05). Patients with high Ube2c expression also showed significantly worse disease-free survival rates than those with low Ube2c expression (p < 0.01). In addition, Ube2c expression was found to be an independent prognostic factor for disease-free survival rate in multivariate analysis. We identified differentially expressed genes between HCC and normal liver tissues. Of those, the Ube2c gene appeared to be associated with HCC progression, and may be useful as a prognostic indicator for HCC patients.