The HLA-DRB4 gene encodes a major histocompatibility complex (MHC) class II molecule involved in antigen presentation to CD4+ T cells, playing a critical role in adaptive immunity. It is part of the HLA-DR family, located on chromosome 6p21. and is tightly linked to HLA-DRB1 and HLA-DQA1/DQB1 loci. HLA-DRB4 is polymorphic, with variations influencing peptide-binding specificity and immune responses. Antibodies targeting HLA-DRB4 typically arise from alloimmunization events, such as blood transfusions, organ transplants, or pregnancy. These antibodies are clinically significant in transplant medicine, where their presence may contribute to graft rejection or failure. In hematopoietic stem cell transplantation, HLA-DRB4 mismatches can trigger immune complications. Additionally, HLA-DRB4 antibodies are implicated in transfusion-related acute lung injury (TRALI) and fetal-neonatal alloimmune disorders. Detection methods, like single-antigen bead assays, help identify HLA-DRB4-specific antibodies for risk stratification. Notably, some HLA-DRB4 alleles (e.g., DRB4*01:01-01:03) exhibit differential immunogenicity, affecting antibody development. Research also explores associations between HLA-DRB4 variants and autoimmune diseases, though its role as an autoantigen remains unclear. Understanding HLA-DRB4 antibody dynamics is vital for improving transplantation outcomes and managing immune-mediated conditions.