To examine leptin’s role in human appetite regulation, we studied recombinant methionyl human leptin’s effects on satiation and satiety in a model of leptin insufficiency, lipodystrophy. Eight females with hypoleptinemia and lipodystrophy were given sc injections of A-100 (maximal dose, 200% of that predicted to normalize serum leptin) for 4 months. Satiation and satiety were determined before and again during leptin treatment. Satiation was measured as the time to voluntary cessation of eating from a standardized food array after a 12-h fast. Satiety was determined as the time to hunger sufficient to consume a full meal after consumption of a standardized preload. During leptin treatment, satiation time decreased (41.2 ± 18.2 to 19.5 ± 10.6 min; P = 0.01), satiety time increased (62.9 ± 64.8 to 137.8 ± 91.6 min; P = 0.04), energy consumed to produce satiation decreased (2034 ± 405 to 1135 ± 432 kcal or 8.5 ± 1.7 to 4.7 ± 1.8 MJ; P < 0.01), and the amount of food desired in the postabsorptive state decreased (P < 0.02). Ghrelin concentrations also decreased during leptin administration (284.3 ± 127.9 to 140.6 ± 104.5 pmol/liter; P < 0.002). We conclude that increased leptin in patients with lipodystrophy results in less caloric, shorter, more satiating meals and longer-lived satiety. These data support the hypothesis that leptin plays an important, permissive role in human appetite regulation.