HLA-B27 is a serologic specificity that encompasses 25 different alleles that encode 23 different products (proteins): HLA-B*2701 to B*2723. These alleles are also called subtypes of HLA-B27, and they may have evolved from the most widespread subtype, B*2705. These subtypes are distinguished from changes mostly in exons 2 and 3, which encode the alpha 1 and alpha 2 domains of the B27 molecule, respectively. Occurrence of ankylosing spondylitis (AS) or related spondyloarthropathy (SpA) has thus far been documented in subjects possessing any one of the first ten (B*2701 to B*2710) subtypes studied. However, B*2706 in Southeast Asian and B*2709 in the Italian island population of Sardinia seem not to be associated with AS. The 13 most recent subtypes have not yet been studied for disease association. It is important to investigate which of them are and are not associated with AS and related SpA, and whether certain subtypes show any preferential association with some of the clinical features or forms of these diseases among the various ethnic/racial populations and geographic regions of the world. This is expected to provide clues as to the mechanism of disease association, and one of the strongest reasons to study the B27 subtypes is to learn the effects of the sequence variations on the peptide-binding specificity of the molecule. Among these peptides may be the putative arthritogenic peptide(s).