Ghrelin, a gastric hormone that stimulates food intake is decreased after ingestion of carbohydrate-rich meals. The acute effect of fat- and protein-rich meals on plasma ghrelin levels is still unknown. Accordingly, plasma ghrelin levels were determined in 10 healthy volunteers after ingestion of the three macronutrients and during vagal stimulation by modified sham feeding and following gastric distension with a highly viscous guar solution. After a solid carbohydrate-rich test meal ghrelin levels fell from 559+/-59.3 pg/ml to a nadir of 449+/-47.4 pg/ml within 60 min (p<0.05). Following an oral glucose load (75 g in 300 ml water), a similar decrease was observed (p<0.05). A fat-rich meal also decreased plasma ghrelin levels (p<0.05) leading to a nadir towards the end of the study period at 180 min. Protein intake, however, stimulated plasma ghrelin levels from 449+/-68.1 to a plateau of 520 pg/ml (p<0.05). There was no significant change of ghrelin levels after modified sham feeding or gastric distension. In conclusion, the decrease of ghrelin levels after fat ingestion shows a different time pattern compared to carbohydrate, while protein ingestion stimulated ghrelin levels. This suggests that different and as yet unknown mechanisms contribute to the regulation of postprandial ghrelin release in man depending on the ingested macronutrients. Cephalic-vagal and intragastric neural mechanisms most likely do not contribute to the postprandial regulation of ghrelin secretion.