The difficulty in maintaining weight loss during obesity treatment may be caused by a counteracting neuroendocrine response. It has been proposed that leptin could be a regulator of this response. We examined the relations between leptin levels during an initial very low calorie diet, other simultaneous endocrine changes, and the 1-yr weight reduction. Sixty-nine obese (24 men and 45 women) were treated with very low calorie diet for 16 weeks, followed by a hypocaloric diet for 32 weeks. Serum levels of leptin, insulin, cortisol, and thyroid hormones were measured at weeks 0, 8, and 18. The relative weight reductions after 18 and 48 weeks were 20.1% and 14.4% in men and 15.4% and 11.8% in women. Low initial leptin levels and large declines in serum leptin were associated with a large 1-yr weight loss in both genders. Leptin levels (baseline or changes) were not independently associated with the changes in insulin, cortisol, or thyroid hormones. Our results may indicate that leptin by itself could be of minor importance for the neuroendocrine response to severe caloric restriction in humans.