In order to investigate the role of cholesteryl ester transfer protein (CETP) in the cholesterolaemic response to dietary fats, we analysed plasma lipid profiles of CETP-transgenic and control C57BL/6 mice fed standard chow (AIN-93G; AIN), a low-fat diet, and diets high in butter (saturated fatty acids; SFA), high-oleic acid safflower oil (monounsaturated fatty acids; MUFA), and safflower oil (polyunsaturated fatty acids; PUFA) for 5 weeks. Each group contained four or five mice. There were significant diet and diet×genotype effects on plasma total cholesterol (TC; P = 0·035 and P = 0·008 respectively), liver TC (P < 0·001 and P = 0·002 respectively), and esterified cholesterol (EC; P = 0·002 and P = 0·001 respectively); diet effects on plasma triacylglycerol (P = 0·007), liver free cholesterol (P < 0·001), and body weight (P = 0·027); a genotype effect on body-weight gain (P = 0·014); and a diet×genotype effect on energy intake (P = 0·006). In transgenic mice the SFA diet caused significantly higher plasma TC than the PUFA diet (P < 0·05). In control mice MUFA and PUFA diets, but not the SFA diet, caused significantly higher plasma TC than the low-fat and AIN diets (P < 0·05). Transgenic mice fed PUFA had lower plasma TC (P = 0·040), while transgenic mice fed MUFA had lower LDL+VLDL-cholesterol (P = 0·013) than controls in the same dietary groups. Transgenic mice fed MUFA and PUFA diets also had significantly higher liver TC (P = 0·020 and P = 0·002 respectively) and EC (P = 0·040 and P = 0·036 respectively) than controls fed the same diets. In the present study we showed that: (1) CETP transgenic mice had a cholesterolaemic response to dietary fats similar to that in human subjects; (2) CETP transgenic mice fed PUFA showed significantly lower plasma TC, while those fed MUFA had lower LDL+VLDL-cholesterol than controls; (3) hepatic accumulation of cholesterol, possibly resulting from the combination of the enhanced cholesteryl ester transfer to apolipoprotein B-containing lipoproteins and increased hepatic uptake of cholesterol, may contribute to the cholesterol-lowering effect of MUFA and PUFA in CETP-transgenic mice; (4) CETP may play a role in appetite and/or energy regulation.