Recent studies on the transcriptional factor ets-1 and carcinoma have shown that ets-1 is linked to carcinoma progression, including tumor invasion and metastasis. We studied the clinical significance of ets-1 in human hepatocellular carcinoma (HCC) by using immunohistochemical staining methods. In 99 HCC cases, the levels of ets-1 expression were analyzed in comparison with various clinicopathologic parameters, such as TNM stage, intrahepatic metastasis, histologic differentiation, and prognosis. Expression of ets-1 was scarcely detected in normal liver but markedly enhanced in noncancerous lesions adjacent to HCC lesions. In HCC lesions, ets-1 expression was observed with high incidence, although the average labeling index (LI) was lower than in noncancerous lesions. However, unexpectedly, the average LI in HCC was lower in cases of high TNM stage, poor differentiation, portal invasion, intrahepatic metastasis, large tumor size, and high Ki-67 LI. Furthermore, cases with high ets-1 expression showed better outcomes for disease-free survival than those with low ets-1 expression by univariate and multivariate analyses. These findings strongly suggest that, unlike in other neoplasms, ets-1 has a crucial role in hepatocarcinogenesis and HCC progression, especially during their early phases.