Objective To analyze the role of adiponectin (APN) in the treatment of ApoE-/- mice with atherosclerosis (AS) and its possible mechanism. Methods Twenty male ApoE-/- mice were enrolled to establish AS model with high-fat diet, and then randomly divided into control group (saline, intraperitoneal injection, 4 weeks) and APN-treated group (25 μg/d, intraperitoneal injection, 4 weeks). HE staining, immunohistochemistry, ELISA, immunofluorescence, reverse transcription PCR and Western blotting were performed to analyze the effect of APN on ApoE-/- mice and the changes of related signaling pathways. Results Compared with the control group, the APN-treated group had smaller atheroma macular areas and lower levels of inflammatory cytokines (IL-8 and TNF-α) in blood vessels. The APN-treated group had less inflammatory cell infiltration in perivascular adipose tissues than those of the control group. The APN-treated group had lower levels of CD86 and IL-1β, but higher levels of CD206 and IL-10 in perivascular adipose tissues than those of the control group. Western blot analysis showed that APN treatment significantly increased the expression of p-STAT6 in perivascular adipose tissues as compared with that of the control group. Conclusion APN has a definitely therapeutic effect on ApoE-/- mice, and the possible mechanism may be associated with the induced macrophage polarization through STST6 signal in perivascular adipose tissues.