Background: Diabetes mellitus is one of the chronic metabolic diseases, which affects about 450 million people in the world with one of them dies every 6 seconds from diabetic related macro and micro-vascular complications as cerebrovascular disease and nephropathy. Aim of the work: This study was designed to investigate the protective effects of pentoxifylline (PTX) on macro-vascular complications as in aorta and renal artery in a streptozotocin induced diabetic rat model. Material and Methods: Forty male albino rats randomly allocated into four groups ten rats each; group I(control group), group II (PTX group), group III (Diabetic group) and group IV (Diabetic + PTX group). Experimental diabetes was induced by single dose of streptozotocin (50 mg/kg) intraperitoneally. PTX and Diabetic + PTX groups received PTX in a single daily dose of (100 mg/kg) in the drinking water. At the end of the study, rats were anaesthetized and aorta and renal artery were extracted for H&E, Orecin and immunohistochemical stains to be examined by light microscope. Results: The main histological alterations in diabetic rat aorta and renal arteries were high significant thickening in the tunica media, smooth muscle proliferation, vacuolation, disruption of elastic fibers in aorta, strong positive reaction of tunica media by anti-NF-κb, and increased thickness of smooth muscle fibers by anti-α-SMA. The Diabetic group treated with pentoxifylline showed significant decrease in these findings. Conclusion: Pentoxifylline can ameliorate the structural changes in blood vessels resulting from diabetes mellitus.