Purpose of Review This publication updates an earlier review on the ever increasing knowledge about genetic polymorphism of HLA-B*27 and discusses its clinical relevance. Recent Findings As of January 1, 2017, there are 213 known alleles of HLA-B*27 at nucleotide sequence level, while at the translated protein level, there are 160 known subtypes based on one or more amino acid sequence differences. Some of these subtypes exhibit differential association with ankylosing spondylitis, and there may even be some level of hierarchy in this regard. On the other hand, HLA-B*27 has a protective effect against HCV, and this effect is also influenced by some of the subtypes of HLA-B*27. This may have important implications for designing anti-viral vaccines for global population and also for developing individualized treatments and vaccines. Summary Disease association and disease protective roles of HLA-B*27 suggest a common ground, i.e., promoting a more pronounced immune/inflammatory response for effective clearance of some pathogens, but that might, on the other hand, lead to autoimmunity and tissue injury in some circumstances.