The hormone leptin profoundly affects body weight and metabolism. Three human adults (two women, 35 and 40 yr old; one man, age 27) have been identified with a recessive mutation in the ob gene, which is homologous to the mutation in ob/ob mice, and produces leptin deficiency and morbid obesity. Because leptin replacement increases brain weight and changes brain protein and DNA content in ob/ob mice, we hypothesized that analogous treatment of leptin-deficient humans would alter brain tissue composition. Volumetric T1-weighted magnetic resonance images of the brain were acquired before and at 6 and 18 months after initiation of replacement therapy (daily sc injections of recombinant methionyl human leptin), which produced dramatic loss in body weight. We used voxel-based morphometry to test for increased gray matter tissue concentration after initiation of leptin replacement and detected increases at 6 months in the anterior cingulate gyrus, the inferior parietal lobule, and the cerebellum. These increases were maintained for over 18 months, with identical stereotaxic coordinates of the maxima for the effects. Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin's influence beyond feeding behavior and endocrine function.