〔Abstract〕 Objective To investigate the effect and mechanism of Ghrelin receptor antagonist(D-Lys3)-GHRP-6 on adipose inflammation and oxidative stress in high fat diet(HFD)-induced obese mice. Methods 4-week old male C57 BL/6 J mice were randomly divided into the normal diet(RD), high-fat diet(HFD) and HFD+(D-Lys3)-GhRP-6 groups. After 16 weeks of feeding, the body weight, body fat rate and body fat composition of mice in each group were analyzed, and the blood and adipose tissue of mice in each group were collected. Mouse monocyte chemokine 1(MCP-1), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) and IL-10 were detected by ELISA. HE staining was used to assess adipocyte diameter and lipid droplet level. Immunofluorescence staining and flow cytometry were used to analyze the number and phenotype of SVF macrophages in adipose tissue. The activities of total superoxide dismutase(SOD), malondialdehyde(MDA), catalase(CAT), xanthine oxidase(XO), glutathione peroxidase(GPx) and XDH in serum of each group were detected. Results Compared with RD group, mice body weight, body fat rate, epididymal white adipose tissue(eWAT), subcutaneous white adipose tissue(sWAT), interscapular brown adipose tissue(iBAT), diameter of fat cells and the fat droplet of iBAT all significantly increased in HFD group. However, the above indexes in HFD+(D-Lys3)-GHRP-6 group were significantly lower than those in HFD group(P<0.05). Compared with HFD group, serum IL-6, TNF-α, MCP-1, MDA, XO and XDH significantly reduced, while the activity of IL-10, SOD, CAT and GPx increased in HFD+(D-Lys3)-GHRP-6 group(P<0.05). In addition, the number of coronary structure(CLS) of eWAT tissue, the total number of macrophages in SVF and the M1 phenotype of macrophages markedly decreased while the M2 phenotype increased in the HFD+(D-Lys3)-GHRP-6 group(P<0.05). Conclusion (D-Lys3)-GhRP-6 may alleviate HFD-induced obesity and adipose inflammation by inhibiting the recruitment of pro-inflammatory macrophages, accelerating their M1-to-M2-phenotype conversion and maintaining the balance of oxidative stress.