SummaryJaundice phototherapy is associated with a significant incidence of watery diarrhea. We have postulated that acute intestinal secretion, rather than malabsorption of dietary carbohydrate, is an effect of a photoproduct of bilirubin upon the intestinal mucosa. Because a major effect of phototherapy is the hepatic excretion of nonconjugated bilirubin, we investigated the effect of bilirubin on small intestinal function in the hamsterin vivo.The entire small intestine was luminally perfusedin vivowith solutions containing bilirubin (0.125 to 0.75 mmole/liter) and net water and sodium fluxes were measured. Control animals absorbed both water (JnetH2O = 58.9 μl/min/g) and sodium (JnetNa= 4.55 μEq/min/g), but animals perfused with bilirubin (≥0.25 mmole/liter) exhibited secretion of water (JnetNa= −39.0 - −85.9) and sodium (JnetNa= −9.91 - −18.24). The rate of water secretion was positively related to the concentration of bilirubin in the infusate (r= 0.749;P< 0.001). The concentration of bilirubin in ultrafiltrates of perfusate was likewise positively related to its concentration in the infusate (r= 0.844;P< 0.001), indicating the potential importance of soluble forms of bilirubin in inducing secretion. Possible epithelial injury was studied by measuring the concentration of DNA in the perfusate and the activity of disaccharidases in postperfusion mucosa, and the possible role of cyclic adenosine monophosphate as a mediator of the secretory process was investigated by determining its concentration in postperfusion mucosa. Perfusion with 0.5 mM bilirubin, which produced significant secretion, did not cause loss of DNA (0.284versus0.244 mg/liter) or mucosal lactase activity (56versus53 units/g) or enhancement of cyclic adenosine monophosphate concentration (14.9versus14.12 pmoles/mg protein).