Leptin-deficient obese mice (ob/ob) have decreased circulating GH and pituitary GH and ghrelin receptor (GHS-R) mRNA levels, while hypothalamic GH-releasing hormone (GHRH) and somatostatin (SST) expression does not differ from lean controls. Given GH is suppressed in diet-induced obesity (a state of hyperleptinemia), it remains to be determined if the absence of leptin contributes to changes in the GH-axis of ob/ob mice. Therefore, to study the impact of leptin replacement on the hypothalamic-pituitary, GH-axis of ob/ob mice, leptin was infused for 7 days (sc), resulting in circulating leptin levels that were similar to wildtype controls (~1 ng/ml). Leptin treatment reduced food intake, body weight and circulating insulin, while elevating circulating n-octanoyl ghrelin concentrations. Leptin treatment did not alter hypothalamic GHRH, SST or GHS-R mRNA levels, compared to vehicle-treated controls. However, leptin significantly increased pituitary GH and GHRH-R expression and tended to enhance circulating GH levels, however this latter effect did not reach statistical significance. In vitro, leptin (1ng/ml, 24h) did not affect pituitary GH, GHRH-R or GHS-R mRNA, but did enhance GH release. The in vivo effects of leptin on circulating hormone and pituitary mRNA levels were not replicated by pair-feeding ob/ob mice to match the food intake of leptin-treated mice. However, leptin did prevent the fall in hypothalamic GHRH mRNA and circulating IGF-I levels observed in pair-fed mice. These results demonstrate that leptin replacement has positive effects on multiple levels of GH-axis function in ob/ob mice.