Aim To test whether the transgenic mice with expressed human SR AI on endothelial cells are susceptible to atherosclerosis on high fat high cholesterol diet (HFHC). Methods TghSR AI+/+, TghSR AI+/ , TghSR AI / from F3 mice and C57BL/6 mice were fed 1.25% cholesterol, 16% fat and 0.5% sodium cholate for 14 weeks. Tissues of heart and aorta, liver, kidney and others from control and transgenic mice were prepared for morphological analysis. To evaluate the degree of atherosclerosis in the transgenic and control mice, atherosclerotic lesions were quantified in the aortic root area with computer assisted image analysis system in all four groups. Results After animals were fed HFHC diet for 14 weeks, extensive atherosclerotic lesions were found at the junction of the aorta to the heart and the aortic sinus, including valve, valve commissures in the aortic wall of TghSR AI+/+ and TghSR AI+/ transgenic mice. Typical lesions of aorta in transgenic mice was stained with oil red O. In TghSR AI+/+ and TghSR AI+/ mice, the mean lesion area per section was 144 864±17 103 μm 2 and 111 323±10 713 μm 2, respectively, p<0.05 (n=6). In TghSR AI / and C57BL/6 mice, the mean lesion area per section was 79 887±9 228 μm 2 vs 66 305±7 991 μm 2, p>0.05 (n=6). However, the lesion area of TghSR AI+/+ and TghSR AI+/ mice was significantly higher than lesion area of TghSR AI / or C57BL/6 mice. Conclusions The transgenic mice are more susceptible to atherosclerosis than C57BL/6 on HFHC diet. These mice may be of value for use as an in vivo test system for studied of pharmacological or genetic interventions of atherosclerosis.