The effects of intravenous and intraduodenal fat on jejunal motility were studied in nine normal volunteers. Using a nitrogen hydraulic infusion system, recording was performed continuously during 4 hr of fasting and 5 hr of 100 ml/hr infusion of fat (Intralipid 10%) given either intraduodenally (group ID) or intravenously (group IV) and 9 hr after the end of fat administration successively. The two experiments were performed at seven-day intervals in random order. In six of the nine subjects, a third experiment, in which 20 g of cholestyramine was given by mouth during intraduodenal fat infusion (group ID + C), was carried out. Venous blood samples were drawn for measurement of serum triglyceride levels and radioimmunoassay of plasma cholecystokinin. Intraduodenal fat, alone or plus cholestyramine, induced a significant reduction in incidence of phase III of the migrating motor complex. Intravenous fat reduced the incidence of phase III. However, this reduction was significant only during the last 3 hr of fat infusion, corresponding to the highest serum triglyceride concentration. In the three groups, fat infusion induced a significant increase in duration of phase II, leading to a postprandial-like pattern. Plasma cholecystokinin increased significantly in the three groups during fat administration, with a significant positive correlation between serum triglyceride concentration and plasma cholecystokinin in the group IV. The data suggest that, in addition to its known inhibitory effects on activity fronts when acting luminally, fat given intravenously may inhibit phase III activity. The effects in both instances may be mediated in part by cholecystokinin.