After vaccination at birth with a yeast-derived second generation hepatitis B virus (HBV) vaccine, children with a Bunun ethnic background have significantly lower levels of protective antibody (anti-HBs) than Han Chinese children, a phenomenon previously observed when other ethnic minority children in Taiwan were given the first-generation plasma-derived HBV vaccine. When serum vitamin A and E levels were measured in these vaccinees, micronutrient deficiency was found not be the cause of this difference in immune response to vaccine. The Bunun children were typed for human leukocyte antigen(HLA) class using a microlymphocytotocixity test. While HLA-A24 was the most prevalent class I serotype in this group , the frequency of HLA-A2 allele was inversely associated with the serum anti-HBs titer (p＜0.01), and HLA-B7 was noted to be associated with HLA-A2. In contrast, the HLA-B27 allele occurred at a higher frequency in the Bunun group and was negative associated with the HLA-A2 allele. Sequence-based HLA typing revealed a highly diverse pattern of A2 alleles, including a rare allele of HKA-A0219, previously found only is South American Indians. However, no specific A2 allele was found to be associated with higher anti-HBs titers in response to HBV vaccine. Thee data suggest a genetic basis for immune responsiveness to HBV vaccine, but the roles of HLA class I molecules require further delineation.