Abstract: Background: Diabetic nephropathy is a microvascular complication of diabetes mellitus, characterized by glomerulur hypertrophy, accumulation of extracellular matrix protein and vascular endothelial dysfunction, progressively leading to glomerulosclerosis, tubulointerstitial fibrosis and proteinuria. The present study investigated the combined effect of lisinopril (ACE inhibitor) and Hemin-Heme oxygenase (HO-1 inducer) in experimental model of advanced diabetic nephropathy. Materials and Methods: Streptozotocin (STZ) (50 mg kg-1 i.p., once) was administered to induce diabetes mellitus. STZ-diabetic rat was subjected to renal ischemia of 30 min to induce advanced nephropathy assessed by measuring serum creatinine, Blood Urea Nitrogen (BUN) and proteinuria. In addition, dyslipidemia, renal oxidative stress, renal lipid profile and also Mean Arterial Blood Pressure (MABP) were noted. Results: Treatment with Hemin (5, 10 and 20 mg kg-1 i.p.) dose-dependently and Lisinopril (1 and 5 mg kg-1 p.o.) significantly but not dose-dependently, attenuated the elevated levels of creatinine, BUN, proteinuria and also improved the both serum and renal lipid profile. Moreover, combination of Lisinopril (1 mg kg-1 p.o.) plus Hemin (5 mg kg-1 i.p.); Lisinopril (5 mg kg-1 p.o.) and Hemin (5 mg kg-1 i.p.) and Lisinopril (5 mg kg-1 p.o.) plus Hemin (20 mg kg-1 i.p.); for 2 weeks was markedly attenuated the increased serum creatinine, BUN, proteinurea, renal oxidative stress, abnormal lipid profiles and MABP, as compared to high dose Lisinopril or Hemin treatment alone, in renal I/R subjected diabetic rat. Conclusion: Thus, it may be concluded that concurrent administration of Hemin and Lisinopril at different dose combination produced a synergistic ameliorative effects in the experimental model of severe diabetic nephropathy which may be due to more effective inhibition of serum and renal lipids, renal oxidative stress and MABP.