Studies in both animals and humans indicate that the autonomic nervous system (ANS) responds to changes in systemic energy balance. In the present study, ANS response to weight change was examined by sequential blockade of cardiac autonomic innervation with parasympathetic (atropine) and sympathetic (esmolol) blockers. Change in heart period (interbeat interval) from baseline after atropine defined the amount of parasympathetic control (PC), and the subsequent change after esmolol defined the amount of sympathetic control (SC). In nonobese subjects, weight gain to 10% above initial body weight resulted in a decrease in PC and an increase in SC, and conversely, weight loss to 10% below initial weight resulted in an increase in PC and a decrease in SC. In obese subjects, weight loss resulted in the same pattern of changes in PC and SC. The major changes were in the parasympathetic arm of the ANS. These findings support the hypothesis that the ANS acts to oppose weight change.