Background & Aims: Previous reports have suggested that the abrogation of gastric inhibitory polypeptide (GIP) signaling could be exploited to prevent and treat obesity and obesity-related disorders in humans. This study was designed to determine whether immunoneutralization of GIP using a newly developed specific mAb would prevent the development of obesity. Methods: A specific mAb directed against the carboxy-terminus of mouse GIP was identified, and its effects on the insulin response to oral and to IP glucose and on weight gain were evaluated. Results: Administration of mAb (30 mg/kg body weight, BW) to mice attenuated the insulin response to oral glucose by 70% and completely eliminated the response to IP glucose co-administered with human GIP. Nine week (wk)-old C57BBL/6 mice injected with GIP mAbs (60 mg/kg BW/wk) for 17 wk gained 46.5% less weight than control mice fed an identical high-fat diet (P=0.00000007). When corrected for BW, no difference in the quantity of food consumed was detected between the two treatment groups. Furthermore, MRI demonstrated that subcutaneous, omental, and hepatic fat were 1.97-, 3.46- and 2.15-fold, respectively, lower in mAb-treated animals compared to controls. Moreover, serum insulin, leptin, total cholesterol (TC), LDL, and triglycerides (TG) were significantly reduced, while the HDL:TC ratio was 1.25-fold higher in treated animals compared to controls. Conclusions: These studies support the hypothesis that a reduction in GIP signaling using a GIP-neutralizing mAb might provide a useful method for the treatment and prevention of obesity and related disorders.