Plasma ghrelin levels are responsive to short- and long-term nutrient fluctuation, rapidly decreasing with food consumption and increasing with food deprivation or weight loss. We hypothesized a vagal contribution to both responses. Nutrient-related ghrelin suppression may be mediated by gastrointestinal load-related vagal afferent activity, or depend upon vagal efferent input to the foregut, where most ghrelin is produced. Similarly, the deprivation-induced ghrelin rise could require state-related vagal afferent or efferent activity. Here, we examined the role of the vagus nerve in the regulation of plasma ghrelin by sampling blood from rats with subdiaphragmatic vagotomy and from sham-operated controls over 48 h of food deprivation, and before and after gastric gavage of liquid diet. Vagotomy affected neither baseline ghrelin levels nor the suppression of ghrelin by a nutrient load. The food deprivation-induced elevation of plasma ghrelin levels ( approximately 160% of baseline), however, was completely prevented by subdiaphragmatic vagotomy. In a separate experiment, the deprivation-related rise in plasma ghrelin was substantially reduced by atropine methyl nitrate treatment, indicating that the response to fasting is driven by increased vagal efferent tone. The dissociation between nutrient load- and deprivation-related ghrelin responses indicates that the regulation of circulating ghrelin levels involves separate mechanisms operating through anatomically distinct pathways.