The close relationship between ankylosing spondylitis and the presence of the transplantation antigen HL-A 27 is well recognized. An attractive explanation for this has been that the gene coding for this antigen exists in marked linkage disequilibrium with an abnormal immune response gene. We have suggested, in contrast, that HL-A 27 may have a more direct importance because of a defective epistatic interaction between the gene coding for this antigen and a distinct disease susceptibility gene for AS, which may therefore be situated some distance from the major histocompatibility complex.