Case-control association study of HBV vaccine response in 574 university students. Conditional analyses identified responsible variants despite broad linkage disequilibrium in HLA. Amino acid variants in HLA-DRβ1 and -DPβ1 were independently associated with response. These variants located in antigen-binding pockets and regulated their physical properties. HBsAg presentation through HLA pocket structures will involve heterogeneity in vaccine response.