The main objective of the study was to examine whether crocetin, a natural product from Gardenia jaminoides Ellis, has beneficial effects on the state of insulin resistance induced by dexamethasone in a rat model. Measured using the oral glucose tolerance tests (OGTT), male Wistar rats treated with subcutaneous dexamethasone (0.08 mg/kg/d) for 6 weeks exhibited reduced insulin sensitivity at weeks 2 and 4 and impaired glucose tolerance at week 4. In the dexamethasone-treated group, serum insulin, free fatty acids (FFA), triglyceride (TG) and tumor necrosis factor (TNF)-α levels were significantly increased at the end of the study. In addition, the hepatic glycogen content was reduced as indicated by periodic acid-Schiff (PAS) staining, and pancreatic islet β cells showed compensatory hyperactivity suggested by immunohistochemical (IHC) staining using an antibody against insulin. Treatment with crocetin (40 mg/kg/d) significantly attenuated all the described effects of dexamethasone. These results suggest that crocetin might prevent the development of dexamethasone-induced insulin resistance and related abnormalities in rats. AUC:area under the curve CON:control CRO(H):high-dose crocetin CRO(L):low-dose crocetin CRO:crocetin DEX:dexamethasone FFA:free fatty acids GAUC:area under the glucose curve HE:hematoxylin-eosin IAUC:area under the insulin curve IHC:immunohistochemical ISI:insulin sensitivity index MET:metformin OGTT:oral glucose tolerance test PAS:periodic acid-Schiff TG:triglyceride TNF:tumor necrosis factor