In order to explore the effect of exposure to subtoxic dose of organophosphorus insecticide chlorpyrifos on the formation of atherosclerosis induced by the high fat diet in New Zealand rabbits and analyze the possible mechanisms, thirty two healthy male New Zealand rabbits were divided randomly into four groups: control, high-fat diet, chlorpyrifos and high-fat diet + chlorpyrifos group. Subtoxic dose of chlorpyrifos (20 mg/kg·d) was administered by lavage every day for six months. The levels of serum fat, activities of cholinesterase and alanine aminotransferase, serum creatinine and blood urea nitrogen were measured respectively. The peritoneal macrophages were assembled and cellular cholesterol efflux was analyzed. Area of atherosclerosis plaque of thoracic aorta was measured by Sudan Ⅳ. Common carotid artery was fixed in formalin, sliced and HE dyed and pathology analysis system was used. The expression of ABCA1 was detected by Real-time PCR and Western blot. Compared with control group, serum TC, LDL and TG were singificantly increased and expressions of ABCA1 in liver, aorta and peritoneal macrophages were markedly increased and cholesterol efflux of peritoneal macrophages was significantly increased in high-fat diet group. There was obvious atherosclerosis lesion in thoracic aorta and common carotid artery in high-fat diet group. Compared with control group, activity of cholinesterase was singificantly decreased, but there were no symptom of intoxation and injury of function of liver and kidney, and level of HDL, expression of ABCA1 and cholesterol efflux were markedly decreased in chlorpyrifos group. Compared with high-fat diet group, activity of cholinesterase was decreased, but there were no symptom of intoxation and injury of function of liver and kidney, and expression of ABCA1 and cholesterol efflux were singificantly decreased, the atherosclerosis lesion areas in thoracic aorta and common carotid artery were increased in high-fat diet + chlorpyrifos group. These results suggest that a long time exposure to subtoxic dose of chlorpyrifos may accelerate formation of atherosclerosis induced by high fat diet in New Zealand rabbits, which the mechanism may be related to the decrease of ABCA1 expression and cholesterol efflux induced by chlorpyrifos.