HLA-C antibodies are part of the human leukocyte antigen (HLA) system, which plays a critical role in immune regulation. HLA-C, a class I MHC molecule, is involved in presenting peptides to cytotoxic T cells and interacts with natural killer (NK) cell receptors to modulate immune responses. Unlike HLA-A and HLA-B, HLA-C exhibits lower cell surface expression but is crucial in pregnancy and transplant immunity. Antibodies against HLA-C typically arise from alloimmunization, such as through blood transfusions, organ transplants, or pregnancy, where maternal exposure to fetal HLA-C triggers an immune response. These antibodies can mediate graft rejection in transplantation by activating complement pathways or promoting antibody-dependent cellular cytotoxicity. In pregnancy, HLA-C antibodies are implicated in complications like recurrent miscarriage or fetal/neonatal alloimmune thrombocytopenia. Clinically, HLA-C antibodies are less frequently detected than other HLA class I antibodies, partly due to historical limitations in testing sensitivity. However, advanced solid-phase assays (e.g., Luminex) now enable precise identification. Their pathogenicity varies; some are benign, while others correlate with poor transplant outcomes or pregnancy disorders. Research continues to clarify their role in immune tolerance and therapeutic strategies to mitigate their effects.