This study investigated the characteristics of obesity induced by a high-fat diet (HD) over 13 weeks in Rhbdf2 gene knockout (KO) mice. Forty 7-week-old Rhbdf2 wild and KO mice were used and the mice were divided into 4 groups: Wild-ND (n=10, Rhbdf2 wild mice, normal diet (ND)), Wild-HD (n=10, Rhbdf2 wild mice, HD), KO-ND (n=10, Rhbdf2 KO mice, ND) and KO-HD (n=10, Rhbdf2 KO mice, HD). The relative epididymal fat weight in KO-HD was significantly increased compared with that in KO-ND (P<0.01). The relative liver and spleen weights in KO-HD were decreased compared with those in Wild-HD (p < 0.05) and KO-ND (p < 0.01). The mRNA expression of SOD1 in KO-ND was significantly reduced compared with that in Wild-ND (p < 0.05). In Wild-ND and HD, the mRNA expressions of TNF-α and IL-6 in epididymal fat were significantly increased compared with those in KO-ND and HD (p < 0.01). A significant increase of TNF- α and IL-6 mRNA expression was observed in KO-HD compared with KO-ND (p < 0.01). These results indicated that Rhbdf2 genes may regulate high fat diet-induced obesity damage by anti-inflammatory and anti-oxidative roles in fat tissue of mice.