The purpose of this study was to determine if increasing dietary fat, either as saturated fat or polyunsaturated fat, would alter initiation of hepatocarcinogenesis by diethylnitrosamine (DEN) or 2-acetylaminofluorene (AAF). Rats were fed one of three purified diets: a low-fat (LF) diet (containing 5% of calories as safflower oil), a high saturated fat (HSF) diet (containing 48% of calories as palm oil) and a high polyunsaturated fat (HPUF) diet (containing 48% of calories as safflower oil). Four weeks later, all rats were subjected to partial hepatectomy (PH). Rats were then divided into four groups and received no carcinogen, DEN (10 mg/kg, p.o., 24 h after PH) or AAF (25 or 100 mg/kg, p.o., 12 h after PH). Five days later, all rats were fed an unrefined diet, and 9 weeks later, all rats were fed phenobarbital in the diet for 26 weeks as a tumor promoter. In rats initiated with DEN, the number of gamma-glutamyl transpeptidase-positive and ATPase-negative foci was higher in the rats fed the HPUF diet, but not the HSF diet, as compared to rats fed the LF diet. The incidence of neoplastic nodules, the mean focal volume and the volume fraction, however, were not significantly altered by dietary fat in DEN-injected rats. The dietary fat content of the diet did not affect the induction of altered hepatic foci or neoplastic nodules in rats initiated with AAF or receiving no initiation. This study shows that initiation of hepatocarcinogenesis can be influenced by dietary fat, but that the effect may be carcinogen-specific.