A minority of red blood cell (RBC) alloantigen–exposed persons form antibodies. Responders are at high risk of developing additional antibodies upon subsequent transfusions. Several studies showed an association between particular HLA‐DRB1 phenotypes and the development of specific RBC antibodies. This study evaluates the presence of HLA‐DRB1 antigens in individuals with single or multiple RBC antibody specificities to explore whether the response against RBC antigens is associated with a summation of particular HLA‐DRB1 susceptibility antigens.

Frequencies of HLA‐DRB1 alleles in individuals with antibodies against clinically relevant antigens were compared to a large population cohort to calculate odds ratios (ORs) for alloimmunization to different RBC antigens.

The study cohort consisted of 941 individuals (female‐to‐male ratio, 3.8) possessing 1462 antibody specificities elicited by transfusion, pregnancy, transplantation, or a combination of these. Besides confirmation of known associations, new associations were identified for anti‐E with DRB1*09 and for anti‐S with DRB1*07 (ORs, 3.7 and 8.7, respectively). Multiple antibody formation was in a minority of cases associated with the presence of multiple DRB1 susceptibility genes. In multiple responders DRB1*15 was present in almost 40% of cases compared to approximately 25% in single‐antibody responders and in the control population.

This study suggests that HLA‐DRB1 restriction plays an important role for a first RBC antibody response but multiple antibody formation seems less dependent on the presence of particular HLA restriction genes, while HLA‐DRB1*15 may represent a susceptibility phenotype enhancing formation of multiple RBC antibody specificities.