Background: It is unknown why some patients with inflammatory bowel disease develop primary sclerosing cholangitis. We have recently shown that patients with primary sclerosing cholangitis have an increased prevalence of mutations in the gene responsible for cystic fibrosis (CFTR) compared to individuals with inflammatory bowel disease alone. Our aim was to examine whether induction of colitis by oral dextran leads to bile duct injury in mice heterozygous or homozygous for mutations in CFTR. The effect of oral administration of docosahexaenoic acid to correct a fatty acid imbalance associated with cystic fibrosis, was also examined to determine if this would prevent bile duct inflammation. Methods: Wild-type mice and mice heterozygous and homozygous for CFTR mutations were given dextran orally for 14 days to induce colitis. Bile duct injury was quantitated by blinded histologic scoring and measurement of serum alkaline phosphatase activity. The effect of pretreating with docosahexaenoic acid for 7 days was examined. Results: Treatment of mice with 100mg/day of dextran for 9 days followed by 85mg/day for 5 days resulted in a significant increase in bile duct injury based on histologic scoring in homozygous cystic fibrosis mice compared to wild type mice (p=0.005). The bile duct injury seen in cystic fibrosis mice was reflected in a 3-fold increase in serum alkaline phosphatase (p=0.0006). Pretreatment with oral docosahexaenoic acid decreased both histologic evidence of bile duct injury as well as serum alkaline phosphatase levels. Conclusions: In the setting of colitis, loss of CFTR function leads to bile duct injury.