HLA-DPB1 is a human leukocyte antigen (HLA) class II gene located on chromosome 6. encoding the beta chain of the HLA-DP heterodimer, which plays a critical role in antigen presentation to CD4+ T cells. Antibodies targeting HLA-DPB1 arise primarily through sensitization events, such as blood transfusions, pregnancy, or prior organ transplants. These antibodies are clinically significant in hematopoietic stem cell transplantation (HSCT), where mismatched HLA-DPB1 alleles between donor and recipient are common. Anti-HLA-DPB1 antibodies are associated with increased risks of graft rejection, graft-versus-host disease (GVHD), and poorer transplant outcomes. Their detection relies on solid-phase assays like single-antigen bead (SAB) technology, which identifies specific antibody reactivities. Unlike HLA-A, -B, or -DR antigens, HLA-DPB1 has historically received less attention in routine HLA matching due to its lower expression and perceived weaker immunogenicity. However, emerging evidence highlights its role in immune-mediated complications, prompting renewed interest in pre-transplant antibody screening and epitope-based matching strategies. Additionally, HLA-DPB1 polymorphisms are linked to autoimmune diseases, suggesting broader implications in dysregulated immune responses. Research continues to explore the balance between HLA-DPB1’s genetic diversity, its functional impact on alloreactivity, and strategies to mitigate antibody-mediated damage in clinical settings.