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We reviewed the initial lipid and fat-soluble vitamin levels in 56 patients with primary sclerosing cholangitis (PSC) enrolled in a randomized, placebo-controlled trial evaluating ursodeoxycholic acid. We also evaluated lipid and vitamin levels in a group of 87 patients with advanced PSC being evaluated for liver transplantation. Of the patients entering the therapeutic trial, 41% had total serum cholesterol levels greater than the 95th percentile, whereas only 20% had high-density lipoprotein cholesterol levels above normal, and only one (2%) had an elevated triglyceride level. Total cholesterol levels were correlated with serum bilirubin levels and were lower in early versus later histologic stages (206 ± 61 vs. 248 ± 79, p = 0.04). Of the 87 pretransplant patients, 29% had elevated serum cholesterol levels and 17% had elevated serum triglyceride levels. Total serum cholesterol levels correlated inversely with total serum bilirubin levels in this group. In patients in the therapeutic trial, vitamin A deficiency was seen in 40%, vitamin D deficiency in 14%, and vitamin E deficiency in 2% of those tested. More prominent deficiencies of fat-soluble vitamins occurred in the pretransplant group of patients, with 82% deficient in vitamin A, 57% deficient in vitamin D, and 43% deficient in vitamin E. We conclude that hypercholesterolemia and fat-soluble vitamin deficiencies are frequent in patients with PSC and are more common with more severe disease. Patients with PSC, especially with advanced liver disease, should be screened for fat-soluble vitamin deficiencies and supplemented accordingly.