Serum leptin concentrations are higher in obese humans than in lean and are decreased by initial weight loss. This study examined the effects of maintenance of weight loss on leptin concentrations and tested whether leptin concentrations at baseline or after initial weight loss are related to the ability to maintain a reduced body weight. Fifty-two overweight women [body mass index (kg/m2) averaging 31.3] were studied before and after a 4 month weight loss program and at 6 month follow-up. Subjects lost 8.1 kg over the 4 month program, and leptin concentrations decreased from 30.1 to 20.4 ng/ml. Initial leptin level per unit body mass index (r = -0.61, p < 0.0001) and weight loss during months 0 to 4 (r = 0.39, p = 0.004) were both significantly associated with initial changes in leptin, and together explained 60% of the variance in change in leptin. Subjects who maintained their weight losses over the 6-month follow-up maintained their reductions in leptin levels; again, weight changes during follow-up were correlated with changes in serum leptin levels (r = 0.41, p = 0.003). There was no evidence that baseline leptin concentration (or leptin/body mass index) or the changes in leptin which accompanied initial weight loss were predictive of subsequent weight regain. Thus, changes in leptin concentration during weight loss track with changes in weight. However, neither baseline concentrations nor initial changes in leptin predict success at weight loss or maintenance.