To investigate the relationship between distribution of human leukocyte antigen alleles and susceptibility to primary biliary cirrhosis among Japanese, we performed serological typing and human leukocyte antigen DP genotyping in 47 Japanese patients with primary biliary cirrhosis. Serologically, the frequency of human leukocyte antigen DQ3 was significantly higher in the patients than in healthy controls, whereas frequency of DR52 was significantly lower in the patients. Human leukocyte antigen DP genotyping using the polymerase chain reaction-restriction-fragment-length polymorphism method showed that the frequency of human leukocyte antigen DPB1*0501 (85.1%) was significantly higher in patients than in healthy controls but that the frequency of DPB1*0402 was significantly lower in patients. The positive association of human leukocyte antigen DPB1*0501 with primary biliary cirrhosis was stronger than that of serological human leukocyte antigen DQ3, which can be explained by its linkage to DPB1*0501. In addition, three of seven DPB1*0501-negative patients had DPB1*0202, suggesting that the human leukocyte antigen DPBl amino-acid chain plays an important role in the immunogenesis of primary biliary cirrhosis among Japanese patients. Comparative analysis of amino acid sequences from DPBl alleles indicated that a Leu at position 35 of the DPBl chain likely contributes to the susceptibility to primary biliary cirrhosis among the Japanese. (HEPATOLOGY 1993; 18: 73-78.) PBC, regarded as an autoimmune disorder, is a chronic, progressive and often fatal nonsuppurative cholangitis accompanied by strong expression of human