Recent studies suggest that leptin may be an important metabolic signal for energy regulation in rodents, but the role of leptin in human energy regulation remains uncertain. Because adaptive variations in energy expenditure play an important role in human energy regulation, we investigated the relationship between leptin and energy expenditure parameters in 61 weight-stable men and women aged 18 years to 81 years who were not obese. Measurements were made of circulating leptin in the fasting state, body fat and fat free mass, resting metabolic rate (n = 61), free-living total energy expenditure (n = 52), and the thermic effect of feeding (n = 33). After statistically accounting for age, body fat, and fat free mass, there was no association between leptin and any measured energy expenditure parameter. In addition, there was no effect of age on the relationship between circulating leptin and body fat mass. These results indicate that physiological variations in circulating leptin are not linked with adaptive variations in energy expenditure in humans, in contrast to indications of this phenomenon in the ob/ob mouse.