Abstract INTRODUCTION: Opioid peptides and exogenous opioids such as morphine have important effects on the cardiovascular system. Today, the opioid system is being considered as a therapeutic target receptor for reducing myocardial ischemia through inhibiting the G protein. Opioid addiction, on the other hand, is one of the major challenges facing humanity and the truth about the effects of opium use on the cardiovascular system is often misted by wrong beliefs. The effect of an exogenous opioid (morphine) on the development and progression of fatty streaks in hypercholesterolemic rabbits was investigated in this study. METHODS: The rabbits were randomly divided into four groups (five in each group): normal, normal + morphine, high-cholesterol, and high-cholesterol + morphine. Biochemical parameters including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), malondialdehyde, triglyceride (TG), fasting blood sugar (FBS), quantitative chronic reactive protein (CRP), coagulation factor VII, fibrinogen, platelet count, RBC count, WBC count and hemoglobin were measured at the start and end of the study. Pathological studies were conducted on the right and left coronary arteries of the animals to look for evidence of fatty streak formation. RESULTS: The results showed that morphine administration along with a normal diet led to a significant increase in levels of cholesterol, coagulation factor VII, and fibrinogen, while enhancing fatty streak formation in the right and left coronary arteries (P<۰.۰۵); it also significantly increased levels of coagulation factor VII, platelets, and weight of rabbits (P<۰.۰۵). However, it had no effect on fatty streak formation in the right and left coronary arteries. CONCLUSION: This study demonstrates that morphine use with both normal and hypercholesterolemic diet increases the risk factors of cardiovascular diseases and atherosclerosis, although it accelerates the development of early atherosclerotic lesions only when administered with normal diet. Keywords: Atherosclerosis, Morphine, High Cholesterol Diet, Animal Study.