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Atherosclerosis is a chronic inflammatory cardiovascular disease with high mortality worldwide. Tofacitinib (CP-690,550), an oral small-molecule Janus kinase inhibitor, has been shown to be effective in the treatment of rheumatoid arthritis, autoimmune encephalomyelitis and ulcerative colitis. However, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of Tofacitinib on atherogenic diet (ATD)-induced atherosclerosis using apolipoprotein E deficient (apoE−/−) mice. Atherosclerosis-prone apoE−/− mice were fed with ATD and treated with or without Tofacitinib through intragastrical administration (10 mg kg−1 day−1) for 8 weeks. Our results showed that Tofacitinib did not change plasma lipids, while significantly reduced the levels of plasma pro-inflammatory cytokines IL-6 and TNF-α. It also significantly attenuated atherosclerotic plaque lesion in the aortic root and macrophages contained in plaque as shown with Mac2 immuno-staining. Peritoneal macrophages (PMC) were separated from apoE−/− mice fed with 8-week ATD, and then subjected to inflammation tests. Flow cytometry analysis of F4/80 and CD206 and mRNA levels of M1 and M2 macrophages markers showed that M1 macrophages decreased while M2 macrophages increased in Tofacitinib treated group. Expressions of other inflammatory genes also indicated an anti-inflammatory status in mice treated with Tofacitinib. Ox-LDL was used to induce foam cell formation from PMC in wild type mice, and the results displayed a reduced formation of foam cells and decreased inflammation in mice with Tofacitinib administration (1 μM). The mRNA and protein levels of ATP binding cassette subfamily A member 1 (ABCA1), a key gene involved in cholesterol efflux, remarkably increased, while it was absence of alterations in scavenger receptors expression. Therefore, we demonstrated that Tofacitinib could attenuate atherosclerosis and foam cells formation by inhibiting inflammation and upregulating ABCA1 expression.