Recombinant hepatitis B (HB) vaccines have successfully reduced infection, cirrhosis and carcinoma, but questions have endured about causality of serious adverse events following vaccination. After an event in a pediatric patient an investigation reviewed HLA vaccine response effects and analyzed genetics in reported cases. There are apparent common causal immune mechanisms among reported adverse events. HLA class II alleles/haplotypes linked to HB vaccine cellular/non-response and Crohn's disease can create conditions that actively/passively amplify, respectively, all or other components of the immune response to the HB vaccine. Presence of the HLA class I allele A2 can result in heavy cytotoxic T-cell activation and vaccine/self-peptide presentation to immune cells. If HLA autoimmune susceptibility alleles/haplotypes are present that control other immune response components, the probability is elevated that these will activate cross-reactive immune cells; the cells, their inflammatory secretions and/or auto-antibodies may initiate adverse events reflecting those susceptibilities. Probable DRB1 amplifying alleles are noted. High-resolution DNA typing and results analysis are described to test the hypothesis in known HB vaccine adverse event patients. Possible practical applications stemming from hypothesis validation are described.