Plasma ghrelin levels are rapidly suppressed by ingestion or gastric delivery of nutrients. Given that the majority of circulating ghrelin appears to be of gastric origin, we addressed the contribution of gastric distention or nutrient sensitivity to this response. Awake, unrestrained rats received intragastric infusions of glucose or water (1 ml/min for 12 min) with gastric emptying either proceeding normally or prevented by inflation of a pyloric cuff. When emptying was permitted, glucose infusion reduced ghrelin level by approximately 50%, and, in agreement with previous data, water infusions were without effect. Ghrelin level was not affected by either infusate when gastric emptying was prevented, thereby discounting a role for gastric distention in the meal-related ghrelin response. That glucose and water infusions were similarly ineffective when the pylorus was occluded shows, further, that gastric chemosensation is not a sufficient trigger for the ghrelin response. We conclude that the meal-related suppression of plasma ghrelin requires postgastric (pre- or postabsorptive) stimulation.