Background and purpose: Mutations in the CFTR chloride channel result in intestinal o-structive episodes in cystic fibrosis (CF) patients and in CF animal models. This study explores the possibility of reducing the frequency of obstructive episodes in the Cftr^-/- mice by the oral application of a gut selective NHE3 inhibitor tenapanor and searches for the underlying mechanisms involved. Experimental approach: Sex and age-matched Cftr^+/+ and Cftr^-/- mice were orally gavaged twice daily with 30mgkg^-1 tenapanor or vehicle for a period of 21 days. Body weight and stool water content was assessed daily and gastrointestinal transit time (GTT) once weekly. The mice were sacrificed when an intestinal obstruction was suspected or after 21 days, and stool and tissues were collected for further analysis. Key results: 21 day tenapanor application resulted in a significant increase in stool water content, stool alkalinity, and a significant decrease in GTT in Cftr^+/+ and Cftr^-/- mice. Tenapanor significantly reduced obstructive episodes to 8% compared to 46% in vehicle treated Cftr^-/- mice and prevented mucosal inflammation. A decrease in cryptal hyperproliferation, mucus accumulation and mucosal mast cell number was also observed in tenapanor compared to vehicle treated unobstructed Cftr^-/- mice. Conclusion and implications: Oral tenapanor application prevented obstructive episodes in CFTR deficient mice and was safe in Cftr^+/+ and Cftr^-/- mice. These results suggest that tenapanor may be a safe and affordable adjunctive therapy in cystic fibrosis patients to alleviate constipation and prevent recurrent DIOS.