BACKGROUND: Extracts of Vernonia amygdalina (V. amygdalina) have been shown to affect the serum lipid profile of some laboratory animals in previous studies. Its impact on serum lipid profile and the histological changes in atherosclerosis has not been studied. Our aim was to determine the effects of V. amygdalina on atherosclerotic lesions induced in rabbits on high-cholesterol diet. METHODS: 18 male rabbits were randomly divided into three groups of control, atherogenic diet, and atherogenic diet + 200 mg/kg of V. amygdalina. The rabbits were fed a normal diet (control group) or a diet supplemented by 0.5% cholesterol and 1% methionine (second and third groups, respectively) for 12 weeks. The fasting sera of all animals were collected at baseline and at the end of the 12 weeks, to determine the levels of lipid profile and the aortas underwent pathomorphological examination. RESULTS: The two groups on the atherogenic diet had significantly increased serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared to the control group. The serum triglyceride (TG) was not statistically different in all three groups. High-density lipoprotein cholesterol (HDL-C) was significantly increased in the V. amygdalina group, compared to the control group but there was no statistically significant difference between the two groups on atherogenic diet. The two groups of rabbits that were on high-cholesterol diet (atherogenic diet group, as well as the atherogenic diet + 200 mg/kg of V. amygdalina) developed histological evidence of atherosclerosis. However, there was no histological difference between the lesions observed in these two groups. CONCLUSION: The use of 200 mg/kg of aqueous extract of V. amygdalina in rabbits did not appear to exert a significant effect on the serum lipid profile. It also did not appear to have any beneficial effect on the development of atherosclerotic lesions.