Disturbances of the intestinal integrity, reflected by an increased intestinal permeability, are reported in cystic fibrosis (CF). Controversy exists whether the increased intestinal permeability is due to CF itself or a consequence of the concomitant exocrine pancreatic insufficiency (PI). We measured intestinal permeability by the sugar absorption test in 32 PI patients: 20 CF-PI, 12 nonCF-PI with chronic pancreatitis, and 50 controls. In the sugar absorption test, the lactulose/mannitol ratio is measured in 5-h urine samples after oral ingestion of a solution of lactulose and mannitol, hyperosmolar by the addition of sucrose. The lactulose/mannitol ratio was increased in both CF-PI and nonCF-PI versus controls (p < 0.0001). In CF, the L/M ratio and permeability for lactulose and mannitol did not change by increasing pancreatic enzyme supplementation by 30-50% for 2 wk (p = 0.74, p = 0.97, p = 0.74, respectively) nor by decreasing the osmolarity of the test solution by 75% (p = 0.24, p = 0.10, p = 0.39, respectively). We conclude that an increased intestinal permeability in CF is probably a consequence of PI and is not related to the dose of pancreatic enzyme supplementation nor the osmolarity of the test solution. The increase is due to an increased permeability for lactulose which might point toward a defect in the tight junctions of the villi and/or crypts. The cause of the increased intestinal permeability in the presence of PI is still unclear. An increased intestinal permeability points toward an impaired functional integrity of the small bowel, which may contribute to gastrointestinal dysfunction in CF.