Two boys with congenital diarrhea, steatorrhea, and growth failure were studied. Preliminary investigations indicated that the enterohepatic circulation of bile acids was interrupted. Radiographically, ileal structure was normal; ileal function was normal when assessed by vitamin B12 absorption. To confirm our clinical suspicion that the patients had an isolated defect of ileal active bile acid transport, peroral terminal ileal biopsies were performed. Ileal mucosa was incubated in vitro in oxygenated Krebs-Ringer bicarbonate buffer containing 10 mM glucose and 0.1, 1.0, or 10.0 mM taurocholic acid at 37 degrees C. Ileal uptake from the patients was 0.10 and 0.34 mumol/g dry wt . min in 0.1 mM taurocholic acid, 1.20 and 2.39 mumol/g dry wt . min in 1.0 mM taurocholic acid, and 21.19 and 11.14 mumol/g dry wt . min in 10.0 mM taurocholic acid. At every concentration, significant (p less than 0.05) reductions were present compared with ileum from 7 ileostomy controls, 0.5 to 27 yr old whose uptake was 1.40 +/- 0.28 mumol/g dry wt . min (mean +/- SEM) at 0.1 mM; 6.36 +/- 1.33 mumol/g dry wt . min at 1.0 mM, and 76.20 +/- 19.30 mumol/g dry wt . min at 10.0 mM taurocholic acid. Ultrastructural examination of the ileal mucosa failed to demonstrate a significant structural abnormality. Significant reduction in ileal uptake of taurocholic acid accompanying clinical and biochemical findings of interruption of the enterohepatic circulation in the absence of mucosal disease suggests that these children have a previously undescribed, congenital transport defect that includes absence of active ileal bile acid transport presenting as diarrhea in infancy.