The etiology and pathogenesis of the inflammatory and fibrotic bile duct lesions characteristic of primary sclerosing cholangitis (PSC) is unknown, but several lines of evidence support the contention that genetic and immunologic factors are involved. There is an association with human leukocyte antigens (HLA) with an increased frequency of DR3, DR6, and DR2 positive haplotypes. DRB3*0101(DR52a) is the most strongly associated allele in some studies, but the HLA gene conferring the primary HLA associated susceptibility to PSC remains to be established. There is an aberrant expression of HLA class II antigens (DR and DP) on bile duct epithelial cells, with the potential to present antigens to the surrounding T-lymphocytes. A defective suppressor T-cell function has been suggested in some studies. The patients may have elevated levels of circulating immune complexes, immunoglobulins, and non-organ-specific autoantibodies. Antibodies to perinuclear antigens (pANCA) are present in about 80% of cases. Increased metabolism of complement C3, reduced clearance of immune complexes, and increased concentration of biliary immune complexes have been found. The strong association between PSC and ulcerative colitis (UC) has not been explained. The detection of circulating IgG antibodies against a specific epitope shared by epithelial cells in the bile ducts and colon in about two-thirds of PSC patients may be of importance. Portal bacteremia secondary to a diseased bowel may possibly contribute to development of liver disease in UC. Viral infections and toxic and ischemic factors have also been implicated in the pathogenesis of PSC. In conclusion, PSC seems to occur in genetically predisposed individuals, mediated by immunologic mechanisms. The primary event triggering the disease development is, however, unknown.