We examined associations between human leukocyte antigen (HLA) class II genes and both rubella-specific immunoglobulin G antibodies and lymphoproliferative responses after measles-mumps-rubella-II (MMR-II) vaccination, in a population-based sample of 346 schoolchildren. The DPB1*0301, DPB1*0401, DPB1*1301, and DPB1*1501 alleles were significantly associated with rubella vaccine-induced antibodies. Alleles suggestive of being positively associated with rubella-specific lymphoproliferative stimulation indices were DPB1*0301, DQB1*0501, DRB1*0101, and DRB1*1104. Conversely, the DPB1*0401, DPB1*1001, DPB1*1101, DQB1*0202, and DRB1*0701 alleles were negatively associated with rubella-specific lymphoproliferation. This study of HLA class II-restricted humoral and cellular immune responses to rubella provides significant insight into mechanisms of vaccine response and new vaccine development.