The diagnosis of small hepatocellular carcinoma (HCC) is sometimes difficult because of the similarity of the histological appearance with adjacent liver tissue. Recent advancement of the quantitative telomerase assay can diagnose small HCC effectively, and the positive rate surpasses those of alpha-fetoprotein and PIVKA-II. The application to a clinical field is, however, limited because the small nodules with the possibility of malignant phenotype tend to be treated easily with ethanol injection therapy without an additional biopsy for this assay only. Further analysis of telomerase related proteins might make it possible to visualize the activity in the tissue sections and expand the usefulness of telomerase as a diagnostic tool in routine clinical use.