Hyperhomocysteinemia is an independent risk factor for multiple cardiovascular diseases. The pathogenesis of homocysteine-induced vascular remodeling has not yet been elucidated. In vivo, we established hyperhomocysteinemia model with high L-methionine diet and found that the accumulation of macrophages, proliferation of VSMCs and decreased expression of A20 in the aorta of mice fed with high methionine diet. In vitro, we found that the overexpression of A20 suppressed the nuclear translocation of NF-kappaB p65 and attenuated homocysteine-induced proliferation and migration of VSMCs. However, down-regulation of A20 reversed the protective effects above. Moreover, A20 attenuated homocysteine-induced vascular remodeling by alleviating the activation of inflammation and suppressing the proliferation and migration of VSMCs through enhanced nuclear translocation of IRF3 and bindingto PPAR-gamma.