Although dehydrated obstructing mucus is thought to account for the obstructive pathology involving the lungs, the pancreas, the reproductive system, and the intestinal tract, its relationship with CF-associated liver disease remains largely hypothetical and little is known about possible risk factors. Complete clinical and autopsy records were available in 38 of 73 deaths occurring over a 10-year period. The liver was normal in only five cases, and they were all infants. Steatosis was the only lesion present in 9, hypoxic liver disease was documented in 8, and biliary cirrhosis in 16 (focal in 10 and multilobular in 6). There was no relationship between the presence of cirrhosis, gallbladder abnormalities, age at death, and clinical status recorded during the year precoding their demise. Mucus plugs characterized by amorphous eosinophilic material within proliferated bile ductules were present in 75% of children with focal or multilobular biliary cirrhosis as opposed to 14% in those without (p = 0.015). A history of meconium ileus or its equivalent was recorded more frequently (p = 0.038) in those with cirrhosis. Finally, biliary cirrhosis was invariably present when there was a history of meconium ileus or its equivalent and when mucus plugs were noted. These findings suggest that patients with intestinal obstruction are at greater risk for the development of cirrhosis and that strategies should be developed to increase the detergent capacity of bile and its flow in order to decrease the viscosity of mucus in the biliary tree.