Previous experimental studies suggest that bile salt-induced colonic fluid secretion is mediated by adenosine 3':5'-phosphate (cyclic AMP). Two biopsy specimens of colonic mucosa were obtained endoscopically before and after different periods of therapy (five, 10, or 15 days), from each of 21 patients receiving chenodeoxycholic acid. A rise of cyclic AMP intracellular levels was found, but only after five and 10 days of treatment was the increase statistically significant when compared with basal levels. Similar changes were observed for guanosine 3':5'-phosphate (cyclic GMP), but percentage increases were higher than for cyclic AMP. Initial diarrhoea disappeared spontaneously, and at 15 days the levels of both cyclic nucleotides were not significantly different from basal levels. Our findings suggest that colonic adaptation to increase in luminal bile salt levels is related to changes in intracellular levels of cyclic nucleotides and support the hypothesis that not only cyclic AMP, but also cyclic GMP may play an important role in producing bile salt-induced diarrhoea in man.