Abstract Cystic fibrosis (CF) is a single-gene disease caused by mutations in the CFTR gene, which result in disrupted chloride secretions with inspissated mucous secretions by exocrine glands. Nick-end labelling was used to assess DNA fragmentation in 14 CF and 24 control duodenal samples, and in two CF and two control lung tissues. In CF small intestine median 46% (range: 30–82) villus enterocytes show DNA fragmentation (vs. 3% (range: 1–7) in controls P<0.001) and median 37.5% (range: 23–79) crypt enterocytes show Ki67 antigen (P<0.001). In CF airways 57% (range: 54–70) of epithelial cells show DNA fragmentation. Inappropriate high DNA fragmentation is a feature of various CF epithelia. This could have great impact in understanding the mechanisms leading to disease.