Spondyloarthropathies (SpA) are a group of chronic rheumatic diseases, which show a strong asoociation with human leukocyte antigen (HLA)-B27. Although the association between HLA-B27 and the susceptibility to SpA was discovered thirty years ago, the exact mechanism by which HLA-B27 predisposes to disease development remains unclear. The classical role of MHC class I molecules is to present peptides for CD8+ T cells. Therefore, it has been proposed that the antigen presenting function of HLA-B27 is somehow altered in the patients developing SpA. However, despite extensive research, the attempts to create a comprehensive theory that would explain the role of HLA-B27 as an antigen presenting molecule in the development of SpA have been unsuccessful. Reactive arthritis (ReA) belongs to the group of SpA. It is a joint inflammation developing after certain bacterial infections e.g. Salmonella, Yersinia, and Chlamydia. Several unrelated observations indicate that HLA-B27 modulates the interaction between ReA-triggering bacteria and host cell. These findings suggest that HLA-B27 may possess functions, which are unrelated to antigen presentation. In this paper, we summarize these findings and discuss their potential impact in the development of SpA.