Abstract： Objective To investigate the effects of fenofibrate on the gene expressions of HNF-4α and HNF-1α in insulin-resistant rats, and to study the relationship between the hypolipidemic effect of fenofibrate and the gene expressions of HNF-4α and HNF-1α. Methods Wistar rats, induced to be insulin resistant by high-fat diet, were gastrically administrated with fenofibrate at the dose of 100 mg·kg-1·d-1 for 2 weeks. Euglycemic-hyperinsulinemic clamp was performed to estimate the insulin sensitivity. Liver mRNA levels of HNF-4α and HNF-1α were measured by RT-PCR assay in rats with IR induced by high-fat diet. Results HNF-4α mRNA level was increased in fenofibrate-treated group than that in untreated group（0.55±0.13 vs 0.44±0.14,P<0.05）, but still lower than that in control group（0.69±0.12,P<0.05）. The glucose infusion rate at 60-120 minutes after insulin infusion (GIR60-120) was higher and body weight gain was lower in fenofibrate-treated group compared with untreated group. HNF-1α mRNA level did not change following the fenofibrate treatment. Conclusion Fenofibrate treatment may partly attenuate the decrease in mRNA level of HNF-4α induced by high-fat feeding, and has no effect on HNF-1α gene expression. Fenofibrate treatment may improve insulin sensitivity and prevent high- fat diet-induced increase of body weight.