Objectives: Cystic fibrosis (CF) is caused by mutations in the gene encoding the CFTR, an ion channel transporting chloride and bicarbonate ions. Patients with CF have stagnant mucus, resulting in insufficient mucus clearance, bacterial infections and lung damage. The main constituent of mucus is secreted, gel forming mucins, stored in goblet cells. Mucus is densely packed in goblet cell granulae, the packing being tightly controlled by the N-terminal part of the mucin and requires calcium ions, as we have shown for the intestinal MUC2 mucin. Properties of mucus expansion in the ileum would presumably be general for all gel forming, secreted mucins, such as MUC5AC in the airways. To increase mucociliary clearance, the usefulness of hypertonic saline (HS) has been investigated in patients with CF at least since 1994, but the mechanism of action remains undetermined. Methods: Using an explant system, we have previously shown that the mucus of the small intestine is easily removable in the WT mouse ileum, whereas it is attached to the epithelium in mice without a functional CFTR channel (CftrDF508). This phenotype could be reverted to a non-attached phenotype by apical solutions containing above 100mM bicarbonate. Results: In the CF mouse ileum, hypertonic saline between 1.75 and 5% detached the mucus from the epithelium. Between 2 and 5% the mucus also expanded over 1 hour. At 2%, HS did not make CftrDF508 ileal mucus penetrable to beads the size of bacteria. Conclusion: HS, a common CF therapy, was effective in detaching the mucus, indicating a mechanism of action. Further research is required to identify the molecular identity of the mucus attachment in CF.