Abstract: Objective: To investigate the prevention effect of insulin resistance by pioglitazone in the rats induced by hight-fat diet. Methods: 45 males Wistar rats including normal group, high fat-fed group, pioglitazone group were used in study. The control rats were fed with common diet. The high fat-fed group were fed with high fat diet containing 59% saturated free fatty acids. The rats of pioglitazone group were fed with pioglitazone 10mg·kg^-1 ·d^-1 with high fat diet. These items were measured in each group at week 11. Results: （1）Compared with the normal group, the body weight at week 4 and blood glucose after 30min, 60 and 120min in oral glucose,the tolenrance test area under the glucose curve, blood glucose after 40min, 90 and 120min of insulin injection subcutaneously and the area under glucose curve in the insulin tolerance,serum insulin, insulin resistance index, serum leptin, serum cholesterol, serum triglyceride and the relative content of visceral fat were significantly increased in high fat-fed group.（2）Compared with these of fat-fed group, the body weight and oral glucose test were decreased in pioglitazone group. Pioglitazone had no effect on fat denaturation of pancreatic tissue. Conclusion: Pioglitazone could prevent the development of insulin resistance of in the rats induced by high-fat diet, and its mechanism was involved the decreasing of serum cholesterol and triglyceride, redistribution of fat tissue.