Oral administration of clonidine blocked diarrhea induced in mice by castor oil, prostaglandin E2, 5-hydroxytryptophan and bethanechol. The antidiarrheal action of clonidine was blocked by yohimbine but not by naloxone, propranolol, prazosin or cimetidine, indicating involvement of the alpha-2 adrenergic agonist activity of clonidine. Other alpha-2 adrenergic agonists (naphazoline, guanabenz, ergometrine, alpha-methylnorepinephrine) were also effective antidiarrheal agents, but alpha-1 (methoxamine, phenylephrine) or beta (isoproterenol) adrenergic agonists were not. Clonidine also blocked normal defecation in mice, an effect which was antagonized by yohimbine. Intracerebroventricular injection of clonidine produced no antidiarrheal effect, suggesting a peripheral site of action. Clonidine inhibited the distension-induced peristaltic reflex in the isolated guinea-pig ileum, an effect which was antagonized by yohimbine. The profound inhibition of peristaltic flow rate was due largely to inhibition of the rate of peristalsis, although an inhibition of the force of peristaltic contractions also contributed. This suggests that the inhibitory effects of alpha-2 adrenergic agonists on intestinal motility are due to the presence of inhibitory alpha-2 adrenergic receptors located on the pacemaker neurons of the enteric nervous system as well as presynaptically on postganglionic neurons innervating intestinal smooth muscle cells.