Steatorrhea persists in most cystic fibrosis patients with exocrine pancreatic insufficiency despite enzyme replacement, perhaps because gastric acid inactivates oral enzymes. Bile acid malabsorption may parallel steatorrhea. We studied the effect of adding cimetidine (300 mg a.c.) to pancreatic enzyme therapy in 8 patients with cystic fibrosis and steatorrhea. Fecal bile acid, weight and fat, and postprandial serum bile acids were measured with and without cimetidine. D-Xylose absorption was normal in all patients. On constant diets, 72-hr stools were collected during enzyme therapy and during a 5-day course of enzymes plus cimetidine. Addition of cimetidine to enzyme decreased fecal weight (257 +/- 32.6 to 198.6 +/- 32.5 g/day), increased the percent of dietary fat absorbed (75.0 +/- 4.9 to 80.1 +/- 4.1%, P less than 0.05), but had no effect on fecal bile acids (4.7 +/- 0.9 to 4.2 +/- 1.0 mmol/m2/day). Compared with no therapy, enzymes increased postprandial serum bile acid at 60 min (9.56 +/- 1.0 to 14.0 +/- 1.3 muM/liter, P less than 0.05) and at 120 min (9.4 +/- 1.2 to 12.4 +/- 1.6 muM/liter, P less than 0.02). The addition of cimetidine to enzymes abolished this postpranidial bile acid rise. In conclusion, addition of cimetidine to oral pancreatic enzyme therapy decreases stool weight and fat but perhaps not stool bile acids in cystic fibrosis. However, correction of fat absorption is incomplete. Enzyme therapy increases postprandial serum bile acids, and this increase is abolished with oral cimetidine. In view of the incomplete correction of steatorrhea and the alterations in serum bile acids induced by cimetidine, further research with this new medication is needed before it can be recommended for routine clinical use in patients with cystic fibrosis.