Objective To explore efficacy of the human RBP-4 vaccine interventions targeting insulin resistance, and provide new ways to treatment of type 2 diabetes. Methods T7 bacteriophage vector expressing human-derived vaccine RBP-4 subcutaneously immunized mice with type 2 diabetes, at the same time set up empty vector group and control group. After the second immunization, detecting humoral immunity levels, fasting plasma glucose value and weight at different time points, and the animals were sacrificed for pathological slice assay at 20 weeks. Results The anti-RBP-4 IgG antibodies induced by RBP-4 vaccine was peaked at 12 weeks, the fasting blood glucose level of immunity group gradual decline from the 8th week to 12 weeks and compared with empty vector group and the control group were significantly different, and always maintain the value(7 mmol/L) or less. During the experiment, mice with type 2 diabetes did not appear straight, vertical hair, scratching nose, convulsions and other obvious abnormalities. The mouse heart, liver, spleen, lung and kidney lesions of Immunization group and vector group have no obviously pathological changes, indicating RBP -4 vaccine safety is good. Conclusion RBP-4 vaccine can significantly reduce fasting blood glucose level in type 2 diabetic mice, it may become a new method in the treatment of insulin resistance.