This is the first large cohort study to report a genetic association between humoral antibody level after measles vaccine and the HLA class II genes. The WHO goal to eradicate measles world-wide magnifies the importance of data relating to the influence of immunogenetics on measles vaccine-induced antibody responses. We present here the analysis of 242 individuals who received one dose of measles-mumps-rubella-II (MMR-II) vaccine at the age of 15 months and were genotyped for HLA class II alleles. These subjects fit into one of three categories; 72 were classified as seronegative, 93 were seropositive and 77 were serohyperpositive. HLA-DRB1*03 (odds ratio (OR), 2.22) and HLA-DPA1*0201 (OR, 1.71) were significantly associated with measles vaccine seronegativity, while additional alleles provided suggestive evidence of association with seronegativity: DQA1*0201, DQB1*0201, and DQA1*0501. The alleles DRB1*03 and DQA1*0201 remained statistically significant after accounting for the effects of other alleles. These findings are crucial in designing both measles eradication by the use of vaccine, and future vaccines to be used in genetically heterozygous populations.