Aim To establish a new transgenic mice model for determining the function and roles of human scavenger receptor A in atherosclerosis in vivo. Methods Human scavenger receptor A-I minigene-driven tie-1 promoter was constructed by endonuclease digestion and confirmed by sequence analysis. Transgenic mice were produced via microinjection method. PCR, Southern blot were used to screen the positive transgenic mice. Transgenic mice line established by mating with C57BL/6 mice and offspring were identified by PCR so as to research transgenic mice transmission. Northern blot, RT-PCR, immunohistochemical analysis, light and transmission electron microscopy were used to investigate the expression location of human SR-A and lesions of arteries and vascular endothelial cells in transgenic mice. Results The fragment sequence of mouse tie-1 promoter and human SR-AI cDNA are similar to their sequences in Genebank and no ATG before the translation initiation sites of human SR-A by sequence analysis. About 3.4 kb tie-1-promoter-hSR-AI-cDNA-BGH polyA fragment were obtained by AatⅡand XhoⅠdigests. 561 survival embryos injected with purified human SR-A minigene were implanted into the oviducts of 19 ICR pseudopregnant mice.Among the 54 survived pups from 13 foster mothers, 7 founders were identified with PCR and Southern blot analysis. Integration rate of exogenous was 13%. PCR positive rates were 47.8%, 71.3%, 75.0% and 100% in G1, G2, G3 and homozygous transgenic mice, respectively. The results of RT-PCR and immunohistochemical analysis showed human SR-A I specifically expressed on endothelial cells of aorta, liver and renal artery of transgenic mice. Plasma triglyceride level of transgenic mice was significantly higher than the level of non-transgenic mice (P<0.05 vs control). There was no difference in total plasma cholesterol level between transgenic and non-transgenic mice. But in transgenic mice, total plasma cholesterol level was significantly higher of males than of females (P<0.01). SEM of the luminal surface of aorta revealed an irregular, elevated bumpy and swelling surface. There was disruption of the endothelial layer and some blood cell was observed adhering to the surface of them in transgenic mice. TEM of aorta of transgenic mice showed that vesicles, multivesicle bodies and swelling mitochondria filled in plasma of endothelial cells. Vacuolar and mucoid degeneration were observed in the media of aortic ardh sections in transgenic mice with HE staining. Conclusions A transgenic mice model with overexpressed human SR-A on ECs were successfully established in this study. The transgene stable inherited across generation after generation. The high level of plasma lipid, hydropic and mucoid degeneration of arterial wall in transgenic mice may accelerate the development of atherosclerosis. Our studies provide a new transgenic model for investigation of the function and roles of SR-A in atherosclerosis.