To determine whether the antidiarrheal effect of loperamide is due to an effect on intestinal motor function or to an acceleration of the rate of absorption by the intestine (as has been suggested recently), we studied absorption during experimental diarrhea produced by the rapid intragastric infusion of electrolyte solution. In studies in which a 2700-ml bolus of electrolyte solution was infused into the stomach over 90 min, loperamide delayed the appearance of rectal effluent in each of 5 subjects and decreased the volume of rectal effluent from 1090 +/- 118 to 770 +/- 73 ml (p = 0.05). When intragastric infusion was continued for 5 h, producing steady-state total gut perfusion, the volume of effluent produced per unit time and the concentration of a nonabsorbable polyethylene glycol marker in rectal effluent was not different with or without loperamide, indicating that loperamide did not alter the rate of absorption by intestinal mucosal cells. Loperamide also had no effect during steady-state perfusion when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. Loperamide did substantially increase the intraluminal volume of the total gut, from 985 +/- 131 to 1764 +/- 195 ml (p less than 0.02). These results suggest that loperamide exerts its antidiarrheal effect by a change in the motor function of the intestine, which results in increased capacitance of the gut and a delay in the passage of fluid through the intestine. This change in motor function, rather than a change in the rate of absorption by intestinal mucosal cells, is responsible for the antidiarrheal effect of loperamide in our experimental diarrhea model.