Apoprotein E biosynthesis was evaluated in the livers of guinea pigs fed chow, 1% cholesterol plus 5% corn oil, or 1% cholesterol plus 5% coconut oil for a period of 12 weeks. Hypercholesterolemia was induced by both experimental diets, although the coconut-oil diet resulted in higher levels. The ratios of free cholesterol/cholesterol ester and of free cholesterol/total phospholipid increased in the plasma of these animals. Peak lipid levels were mostly achieved by 8 weeks of diet. Both cholesterol and triglyceride were substantially increased in the liver of animals fed the experimental diets, while phospholipid content was unchanged. The amount of apoprotein E mRNA in the guinea pig livers was evaluated by cell free translation assays and by membrane hybridization. The livers of animals fed corn oil with cholesterol for 4 weeks or 8 weeks contained 2 to 2.5 more apoprotein E mRNA compared to the control livers. With the diet containing coconut oil with cholesterol, the hepatic apoprotein E mRNA increased somewhat later, so that by 8 weeks it was 1.7- to 1.9-fold higher than in the control animals. We conclude that high cholesterol diets, when fed as part of a high saturated or polyunsaturated fat diet, lead to increased hepatic apo E mRNA abundance. The relationship between the increased apo E mRNA levels and the previously described increases in apo E synthesis and circulating apo E levels is discussed.