The modifying effect of dietary protocatechuic acid (PCA) given during the initiation phase or the postinitiation phase on liver carcinogenesis induced by diethylnitrosamine (DEN) was studied in male F344 rats. At 6 weeks of age, rats were divided into experimental and control groups and fed the diets containing 500 and 1000 ppm PCA or the basal diet. At 7 weeks of age, all animals except PCA alone and control groups were given DEN at 40 ppm in the drinking water for 5 weeks to induce liver cell neoplasms. Seven days after the DEN exposure, groups of animals fed the PCA diets and continued on these diets until the end of the study. All animals were necropsied during the 37 weeks after the start of the experiment in order to determine the incidences of preneoplastic liver cell foci and neoplasms. Hepatic ornithine decarboxylase activity was also measured in all animals at the termination of the study. Dietary PCA administered at both doses during the initiation phase significantly inhibited the incidence of altered hepatocellular foci resistant for iron accumulation or those positive for glutathione S-transferase placental form and the liver cell tumor incidence and multiplicity. Similarly, the numbers of liver cell foci and neoplasms and tumor multiplicity were significantly reduced in groups fed the PCA diets at the postinitiation stage of carcinogenesis. Hepatic ornithine decarboxylase activity was reduced in DEN-treated animals fed the PCA diets compared to those given DEN alone. Although the precise mechanisms of PCA-induced inhibition of hepatocarcinogenesis remain to be elucidate, it is likely that the inhibitory effects during the initiation and postinitiation phases may be due to alteration in hepatic ornithine decarboxylase activity under the present experimental condition.