Length of terminal restriction fragments (TRFs) was examined in 34 samples from hepatocellular carcinoma (HCC) patients. TRF length alterations (reduction or elongation) were found in 18 of 34 (53%) HCC nodules (13 cases reduced, 5 cases elongated). The incidence of TRF alteration was significantly higher in HCC exceeding 3 cm in diameter, moderately- or poorly-differentiated in histology, or with microscopic aggressive lesions (P<0.05). The survival rates were significantly higher in patients without alterations in TRFs (P<0.05). Specifically, all 5 cases with elongated TRFs recurred within 1 year after resection and had a poor prognosis. In contrast, the presence of telomerase activity was not associated with alterations in TRF length. The incidence of TRF length alterations increased with HCC tumor progression.