Accumulation of genetic alterations in hepatocarcinogenesis is closely associated with chronic inflammatory liver disease. 8-oxo-2-deoxyguanosine (8-oxo-dG), the major promutagenic DNA adduct caused by reactive oxygen species (ROS), leads to G:C 3 T:A transversions. These lesions can be enzymatically repaired mainly by human MutT homolog 1 (hMTH1), human 8-oxo-guanine DNA glycosylase (hOGG1) and human MutY homolog (hMYH). The aim of this study was to evaluate the extent of oxidative damage and its dependence on the cellular antioxidative capacity and the expression of specific DNA repair enzymes in tumor (tu) and corresponding adjacent nontumor (ntu) liver tissue of 23 patients with histologically confirmed hepatocellular carcinoma. 8-oxo-dG levels, as detected by high-pressure liquid chromatography with electrochemical detection, were significantly (P ؍ .003) elevated in ntu tissue (median, 129 fmol/g DNA) as compared to tu tissue (median, 52 fmol/g DNA), and were closely associated with inflammatory infiltration. In ntu tissue, the hepatic iron concentration and malondialdehyde levels were significantly (P ؍ .001) higher as compared to tu tissue. Glutathione content, glutathione peroxidase activity and manganese superoxide dismutase messenger RNA (mRNA) expression did not show statistical differences between ntu and tu tissue. Real-time reverse transcription polymerase chain reaction revealed in tu tissue significantly (P ؍ .014) higher hMTH1 mRNA expression compared to ntu tissue. In contrast, hMYH mRNA expression was significantly (P < .05) higher in ntu tissue. No difference in hOGG1 mRNA expression was seen between tu and ntu. In conclusion, these data suggest that ROS generated by chronic inflammation contribute to human hepatocarcinogenesis. The role of DNA repair enzymes appears to be of reactive rather than causative manner. (HEPATOLOGY 2004;39:1663-1672.) E pidemiological studies have demonstrated a striking correlation between chronic inflammatory liver diseases such as hepatitis B virus or hepatitis C virus (HCV) infection and the occurrence of hepatocellular carcinoma (HCC). Hepatocarcinogenesis is a multistep process that involves the accumulation of both genetic and epigenetic events such as point mutations, gross chromosomal rearrangements, oncogene activation, and tumor suppressor gene inactivation. 1 Reactive oxygen species (ROS) have been implicated in the pathogenesis of degenerative and inflammatory diseases, aging, and cancer. 2 In liver disease, infiltration of activated phagocytic cells provides an additional source of ROS production that promotes oxidative stress and damage to proteins, lipids, and DNA. 3 8-oxo-2Ј-deoxyguanosine (8-oxo-dG), one of the major and most deleterious DNA base lesions, is induced by the attack of either hydroxyl radical or singlet oxygen on deoxyguanosine. 4 8-oxo-dG is a promutagenic lesion as it mispairs preferentially with adenine