Cholesterol in High density lipoproteins (HDL) and apolipoprotein (apo) A-I levels are inversely correlated with coronary heart diseases. Overexpression of human apoA-I in several strains of mice has been shown to protect against atherosclerosis development. However, lipoprotein metabolism in mice are far from that in human. Concerning this aspect, the rabbit model presents several advantages with the presence of cholesteryl ester transfer protein or with the apoB-containing lipoproteins as major cholesterol carriers in plasma. Therefore, in order to study the role of apoA-I in lipoprotein metabolism and assess its efficacy to retard atherosclerosis progression in another animal model, we produced human apoA-I transgenic rabbits (New Zealand White background, NZW) with the use of an 11-kb genomic apoA-I fragment containing a liver-specific promoter. Transgenic animals expressed human transgene in the liver whereas, in rabbits, apoA-I is normally produced by the intestine. In one of five transgenic lines established, human apoA-I concentration was superior to 175 mg/dl whereas rabbit apoA-I levels were significantly reduced. In this line, HDL-cholesterol levels were 2-fold increased in comparison with that of non transgenic littermate. Protective effect of apoA-I overexpression was evaluated in rabbits fed a cholesterol rich diet for 14 weeks. Plasma levels of atherogenic apoB-containing lipoproteins (>1000 mg/dl) were matched between transgenic and control animals. HDL-cholesterol levels in transgenic rabbits were still approximately twice that of the control rabbits. At the end of the experiment, the amount of aortic surface area covered by the lesions as well as the amount of lipid accumulation in the aorta were significantly less in transgenic rabbits compared with control rabbits, confirming the beneficial properties of apoA-I-containing lipoproteins. Furthermore, human apoA-I transgenic rabbits were crossed with Watanabe rabbits, a relevant model of familial hypercholesterolemia, which develop spontaneously severe atherosclerosis. Human apoA-I levels in human apoA-I Watanabe rabbits, 101 mg/dl, were lower than that in transgenic NZW rabbits. Rabbit apoA-I levels were similar between human apoA-I Watanabe rabbits and control rabbits. However, HDL-cholesterol concentration were still 2-fold higher in transgenic versus non transgenic Watanabe rabbits. These data established the fundamental role of apoA-I in HDL metabolism and in the atherosclerosis process.