The etiopathogenesis of extrahepatic biliary atresia (EHBA) remains undefined. There are clinical and pathological suggestions supporting the idea that EHBA could consist of at least two forms: the congenital (embryonic or fetal) and the acquired (perinatal) types. To test the hypothesis that susceptibility to this disease would be influenced by host genetic factors, we studied the human leukocyte antigen (HLA) system in 55 patients with and without major extrahepatic congenital anomalies. We found, especially in those without associated malformations, a significantly higher frequency of HLA-B12, of haplotypes A9-B5 and A28-B35, and of their disequilibrium values, as compared with the 8th International Histocompatibility Workshop controls. This study suggests that immunogenetic factors may play a role in determining susceptibility to EHBA, and the different HLA frequencies in those with and without anomalies lend support to the hypothesis that biliary atresia may be an etiologically heterogeneous disorder.