The goal of this study was to assess the relationship between the degree of irregular regeneration of hepatocytes (IR) and the development of hepatocellular carcinoma (HCC). We examined the liver biopsy specimens from patients with chronic liver disease (CLD), and the noncancerous liver tissue in the surgically resected specimens from patients with HCC. Liver tissues were obtained from 18 patients with B-viral CLD, 38 with C-viral CLD, and 5 with nonB-nonC (NBNC)-CLD who underwent liver biopsy, and 24 patients with B-viral HCC, 67 with C-viral HCC, and 17 with NBNC-HCC who underwent surgical resection. The IR score of the noncancerous region of the liver of the HCC patients and that of the liver biopsy specimens of the CLD patients, were compared. Of the 108 samples of noncancerous liver tissue from the HCC patients, 70% showed an IR score of moderate or higher (IR = 3 or 4), and only 1.9% showed an IR score of none or minimal (IR = 0 or 1). The degree of IR of hepatocytes in the HCC patients was significantly more severe than that in the CLD patients in each etiological type of CLD. High IR may reflect the histologic expression of genetic instability, namely a carcinogenic state, although prospective studies are needed to determine its relationship to the risk for developing HCC.