Abstract: ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI/CLA-1) are the key proteins in reverse cholesterol transport (RCT). The high expression of ABCA1 and SR-BI/CLA-1 can decrease the danger of atherosclerosis. The purpose of the study is to find ABCA1 and CLA-1 up-regulators for treating atherosclerosis by using cell-based high throughput screening models. Among 20 000 compounds screened, E0869 1-(3, 4-dimethylphenyl)-1-oxopropan-2-yl 4-((methylsulfonyl)methyl)benzoate was found as the positive hit. The up-regulated activities of E0869 in ABCA1p-LUC and CLA-1p-LUC HepG2 cell were 160% and 175%, respectively. The EC₅₀ values of E0869 in ABCA1p-LUC and CLA-1p-LUC HepG2 cell were 3.79 and 1.42 μmol·L^-1, respectively. E0869 could upregulate the mRNA and protein levels of ABCA1, SR-BI/CLA-1 and ABCG1 genes in HepG2 and RAW264.7 cells by Real-Time Quantitative PCR and Western blotting analysis, but could not influence the expression of FAS, SREBP-1c and CD36. Foam cell assay showed that E0869 could inhibit lipids accumulation in mouse peritoneal macrophages RAW264.7. Cholesterol efflux assay showed that E0869 could induce HDL-mediated cholesterol efflux in mouse peritoneal macrophages RAW264.7. In conclusion, E0869 could up-regulate ABCA1 and CLA-1 activity, and had good anti-atherosclerotic activity in vitro.