Human leukocyte antigen c (HLA-C) is a polymorphic membrane protein encoded by the HLA-C gene in the class I major histocompatibility complex. HLA-C plays an essential role in protection against cancer and viruses but has also been implicated in allograft rejection, preeclampsia, and autoimmune disease. This review summarizes reports and proposed mechanisms for the accessory role of HLA-C in rheumatic diseases. Historically, contributions of HLA-C to rheumatic diseases were eclipsed by the stronger association with HLA-DRB1 alleles containing the “shared epitope” with rheumatoid arthritis. Larger genetic association studies and more powerful analytical approaches have revealed independent associations of HLA-C with rheumatic disease–associated phenotypes, including development of anticitrullinated peptide antibodies. HLA-C functions by presenting antigens to T cells and by binding activatory and inhibitory receptors on natural killer (NK) cells, but the exact mechanisms by which the HLA-C locus contributes to autoimmunity are largely undefined. Studies have suggested that HLA-C and NK cell receptor polymorphisms may predict responsiveness to pharmacotherapy. Understanding the mechanisms of the role of HLA-C in rheumatic disease could uncover therapeutic targets or guide precision pharmacologic treatments.