Obesity is a high risk factor in the development of insulin resistance and type 2 diabetes. Obesity increases macrophage infiltration into adipocyte and overproduction proinflammatory cytokines that leads to development of insulin resistance. T cell also plays an important role link between obesity and insulin resistance. CC-chemokine ligand 5 (RANTES) is a chemokine secret by T cells, eosinophils, and basophils, and plays an active role in recruiting leukocytes thus trigger sever inflammation. The CC-chemokine receptor 5 (CCR5) interactions with RANTES and mediates activation of T lymphocytes and macrophages by chemokines. It has been demonstrated high-fat diet-induced obesity, adipose inflammation, and insulin resistant could be attenuated in CCR5 knockout mice. Since the level of inflammation is also influenced by the difference of gender. Thus, the present study was aimed to investigate whether CCR5 knockout mice protect against high-fat diet (HFD)-induced obesity and insulin resistance has gender difference. C57Bl/6 male and female mice were fed with HFD for 24 weeks to induction of obesity and insulin resistance. The HFD mice developed insulin resistant syndrome characterized by elevated body weight, hyperglycemia, hyperinsulinemia, and hyperlipidemia. In addition, HFD mice exhibited impairment of oral glucose tolerance test (OGTT), increasing of glucose-stimulated insulin secretion, and decreasing of insulin sensitivity during insulin tolerance test (ITT). CCR5-/- attenuated diet induced obesity and glucose stimulate insulin secretion especially in female mice. The insulin sensitivity is improved only on CCR5-/- female mice during insulin tolerance test. Deficiency of CCR5 also attenuated obesity-induced fatty liver. The weights of fat pads were significantly decreased in CCR5-/-male and dramatic reduced in female mice. In addition, our results show that the insulin receptor protein level was reduced in liver of HF mice. CCR5-/- female mice increased protein expression of insulin receptor and Akt threonine phosphorylation. These results indicate that CCR5 deficiency protect against high-fat diet-induced obesity and insulin resistance especially in female mice.