HLA markers of the class II region are important for determination of the predisposition to RA, clinical manifestations, and rate of progression of joint destruction in this autoimmune disease. Furthermore, evidence emerges indicating that HLA markers also have an impact on treatment outcome in RA. Currently, several immunopathogenetic models of HLA-dependent influences in RA are under debate. These models insufficiently explain the graded influence of HLA-DR and HLA-DQ on manifestation and joint destruction, however. Currently, there is not enough evidence to unequivocally identify a primary susceptibility locus or to pinpoint the HLA-dependent mechanism in RA. Overall, the influence of HLA class II markers on disease susceptibility is rather restricted, and, in turn, their utility in establishing the diagnosis of RA is of limited use. Although relative risks are higher for the association of particular genotypes with extra-articular forms of RA, HLA genotyping may not contribute to prognostication in individual patients but may aid in disease stratification. In contrast, HLA genotyping in early RA, particularly when combined with the determination of RFs and determination of the presence of bony erosions, is of value to identify patients at risk for poor outcome. In turn, these patients may benefit from early aggressive therapy, and HLA genotyping should be useful to aid in risk stratification in patients and thus helpful for the choice of treatment. Lastly, disease and risk stratification based on HLA markers along with the elucidation of HLA-dependent mechanisms may facilitate the development of specific immunotherapy modalities.