Liver cholestasis can be a life-threatening complication during home parenteral nutrition and may lead to combined liver-intestinal transplantation. To assess the prevalence of home parenteral nutrition-related liver disease and its contributing factors in patients with permanent intestinal failure. Prospective cohort study. Two approved home parenteral nutrition centers. 90 patients with permanent intestinal failure who were receiving home parenteral nutrition were enrolled from 1985 to 1996. Clinical, biological, endoscopic, and ultrasonographic follow-up. Histologic examination of the liver was done in 57 patients (112 liver biopsies). The Kaplan-Meier method was used to determine the actuarial occurrence of chronic cholestasis and complicated home parenteral nutrition-related liver disease (bilirubin level ≥ 60 µmol/L [3.5 mg/dL], factor V level ≤ 50%, portal hypertension, encephalopathy, ascites, gastrointestinal bleeding, or histologically proven extensive fibrosis or cirrhosis). Contributing factors were assessed by using univariate and multivariate (Cox model) analysis. 58 patients (65%) developed chronic cholestasis after a median of 6 months (range, 3 to 132 months), and 37 (41.5%) developed complicated home parenteral nutrition-related liver disease after a median of 17 months (range, 2 to 155 months). Of these patients, 17 showed extensive fibrosis after 26 months (range, 2 to 148 months) and 5 had cirrhosis after 37 months (range, 26 to 77 months). The prevalence of complicated home parenteral nutrition-related liver disease was 26% ± 9% at 2 years and 50% ± 13% at 6 years. Six patients died of liver disease (22% of all deaths). In multivariate analysis, chronic cholestasis was significantly associated with a parenteral nutrition-independent risk for liver disease, a bowel remnant shorter than 50 cm in length, and a parenteral lipid intake of 1 g/kg of body weight per day or more (ω-6-rich long-chain triglycerides), whereas complicated home parenteral nutrition-related liver disease was significantly associated with chronic cholestasis and lipid parenteral intake of 1 g/kg per day or more. The prevalence of complicated home parenteral nutrition-related liver disease increased with longer duration of parenteral nutrition. This condition was one of the main causes of death in patients with permanent intestinal failure. Parenteral intake of ω-6-rich long-chain triglycerides lipid emulsion consisting of less than 1 g/kg per day is recommended in these patients.