DDT is known as a nongenotoxic hepatocarcinogen and has been shown to induce microsomal enzymes and GGT-positive foci and to inhibit gap junctional intercellular communication (GJIC) in the rodent liver. In consideration of these findings, we examined time-related changes in potential factors including hepatic enzyme induction, oxidative stress, cell proliferation, and GJIC in a 4-week and a 2-year feeding studies of p,p'-DDT with F344 rats. Consequently, hepatic microsomal P450 isozymes such as CYP2B1 and CYP3A2 were induced from the beginning of treatment in a dose-dependent manner. Measurement of oxidative stress markers revealed significant increases in lipid peroxide and 8-hydroxydeoxyguanosine at dose levels that induced hepatocellular tumors. Cell proliferation was enhanced within 3 days at any dose level, but returned to normal after 7 days and no significant changes thereafter. GJIC was inhibited throughout the study from the beginning to the end of treatment. Histologically, eosinophilic foci appeared earlier than controls and increased in number and size prior to development of hepatocellular tumors. These results indicate that DDT may induce eosinophilic foci as a result of oxidative DNA damage and leads them to neoplasia in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.