The present investigation was conducted to determine (1) if hepatomegalic and mitogenic effects of selected hypolipidemic peroxisome proliferators are associated with an elevation of hepatic ornithine decarboxylase (ODC) levels and (2) if induction of ODC is a specific event associated with the development of preneoplastic hepatocellular foci and the eventual formation of hepatomas. Following a single i.p. dose of Wy-14,643 (Wy), the hepatic ODC activity in rats rose sharply, reaching a peak at 8 h, and returned to the normal level by 24 h. Other peroxisome proliferators tested (methyl clofenapate, BR-931 and nafenopin) also increased the hepatic ODC activities significantly 8 h after i.p.. administration of a single dose. Continuous dietary administration of Wy, whether or not these animals were previously initiated with the carcinogen diethylnitrosamine (DEN), resulted in a sustained elevation of hepatic ODC activity. Although Wy exerted an enhancing effect on DEN-initiated tumorigenesis, there was no additional increase of ODC activity. There was no correlation between the level of ODC induction and the presence or absence of altered liver cell foci. These results suggest that induction of ODC by peroxisome proliferators is not a specific event associated with the development of preneoplastic foci and hepatocarcinogenesis, but is an event associated with the sustained maintenance of hepatomegaly and and increased liver cell proliferation.