Background: Erythropoietin (EPO) and exendin-4 are widely used intreatment of type 2 diabetes and enhance the general and metabolic conditions in diabetic patients. Objective: Assessing the effect of erythropoietin and exendin-4 administration on experimental diabetic adult male albino rats. Design: experimental design. Materials and Methods: Forty adult male albino rats of local strain were housed in 8 suitable metal cages (20 ×32× 20 cm for every 5 rats). They were divided into five equal groups: Group I served as a control group, group II was diabetic control, group III was diabetic group-treated with erythropoietin subcutaneously in a dose of 300 uint/kg 3 times a week for 4 weeks, group IV was diabetic group received exendin-4 intraperitonealy in a dose of 1 microgram /kg once daily for one week  period, and groupV was diabetic-treated with both drugs. Blood samples were collected for measuring fasting glucose, fasting insulin , cholesterol(CHO), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), high density lipoproteins cholesterol (HDL-c), and hematological parametres: hematocrite value , hemoglobin content, red blood cells (RBCs) and white blood cells (WBCs) .      After induction of diabetes by alloxan, the first diabetic  group was kept diabetic without any treatment (diabetic control G II) , the second diabetic group was treated with erythropoietin subcutaneously in a dose of 300 uint/kg 3 times a week for 4 weeks (G III), the third diabetic group was treated with exendin-4 intraperitonealy in a dose of 1 microgram /kg once daily for one week (G IV), and the fourth diabetic group of rats was treated with both drugs (G V). Results: Alloxan-induced diabetes mellitus was associated with significant higher levels of blood glucose, total cholesterol, triglycerides and  LDL, and significantly lower levels of, insulin, , HDL and hematological parameters (HV,HB%,RBCs,WBCs)  as compared with normal control group. Erythropoietin injection in diabetic rats  produced significant lower levels of blood glucose, total cholesterol,  triglycerides and LDL, with significantly higher  levels of insulin, HDL and hematological parameters  as compared with control diabetic group. Exendin-4 showed significant lower levels of  blood glucose, total cholesterol and TG, and significant higher levels of HDL, and insignificant results on insulin and  hematological parameters  as compared with the control diabetic rats. Treatment of rats with erythropoeitin and exendin-4 resulted in significant lower levels of blood glucose, total cholesterol and  LDL, and significant high levels of insulin, HDL and hematological parameters as compared with control and other groups . Conclusion: Erythropoietin and exendin-4 were more potent in reducing hyperglycemia than the effect of each one separately. Erythropoietin improved the general condition of  diabetic rats due to its hematopoitic  effect.