Background: Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Objective: To evaluate the effects of leptin on insulin resistance. Research Design and Methods: Three leptin-deficient adults (male, 32yo, BMI 23.4kg/m²; female, 42yo, BMI 25.1kg/m²; female, 46yo, BMI 31.7kg/m²) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTT), while patients were on r-metHuLeptin and after treatment was interrupted for 2 to 4 weeks, on the 4th, 5th and 6th year of treatment. Results: At baseline, all patients had normal insulin levels, C-peptide and homeostatic model assessment of insulin resistance index, except a female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03±3.27 vs. 8.16±2.77 mg/kg/min, p=0.0016) but did not differ on the 4^th, 5^th and 6^th year of treatment when all results were analyzed by a mixed model (F(1,4)=0.57 and p= 0.5951). The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction, attributed to increased post-hepatic insulin delivery and sensitivity. Conclusions: In leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.