Certain nonsteroidal anti-inflammatory drugs (NSAID) of the fenamate chemical class are known to cause diarrhea in clinical use. Paradoxically, this action is shared by prostaglandins, against whose syntheses are inhibited by NSAID. This study was done to investigate the laxative potential of 5 NSAID (meclofenamate, flufenamate, mefenamate, indomethacin and aspirin). The ability to produce a laxative response was assessed by determining effects on fluid absorption in vitro in hamster everted sacs and by the enteropooling assay in hamster small intestine. In addition, the lytic action of these drugs on the erythrocyte membrane was determined to arrive at a possible mechanism of action. All of the NSAID, except aspirin, produced dose-related inhibition of fluid transport, similar to prostaglandin E1 and E2. The order of inhibition was flufenamate greater than meclofenamate greater than mefenamate greater than indomethacin. Like results were obtained when enteropooling was measured in vivo. Flufenamate and meclofenamate produced lumenal fluid accumulation comparable to two laxatives, dioctyl sodium sulfosuccinate and ricinoleic acid. Finally, the effects of these NSAID on fluid movement paralleled their lytic action on the erythrocyte membrane model, suggesting that NSAID may produce diarrhea in a manner similar to certain laxatives, by increasing mucosal permeability through membrane damage.