Smokers weigh less than age-matched nonsmokers, and most smokers gain weight after smoking cessation due to an increase in food intake and a decrease in energy expenditure. Leptin is an endocrine signal thought to regulate body fat stores through hypothalamic control of energy intake and expenditure. To determine whether the "weight-reducing" effects of smoking may be mediated by leptin, we measured plasma leptin concentrations in 22 middle-aged and older male smokers (body mass index [BMI], 28 +/- 1 kg/m2, mean +/- SEM) and 22 nonsmokers matched to the smokers for age (64 +/- 1 years) and BMI (28 +/- 1 kg/m2). The body weight and leptin concentration were remeasured at 3 and 6 months in 13 of the smokers who successfully stopped smoking. The leptin concentration correlated positively with the BMI in both smokers (r = .74, P < .001) and nonsmokers (r = .76, P < .001). However, the intercept of the regression line was higher for smokers versus nonsmokers (P < .05), with no difference in the slope. Thus, male smokers have a higher leptin level for a given BMI than nonsmokers. Following 6 months of smoking cessation, body weight increased by 7% (6.0 +/- 0.1 kg, n = 13, P < .01). Despite this weight gain, the mean leptin concentration did not increase with smoking cessation. On average, leptin levels were 25% lower than would be expected for the amount of weight gained after smoking cessation. These findings suggest that cigarette smoking directly elevates circulating plasma leptin concentrations, and this increase may be one mechanism for the lower body weight of smokers compared with nonsmokers.