After two decades of research involving thousands of RA patients, it is still not possible to precisely define the relation of HLA-DRB1 SE alleles to RA severity. Improvements in our understanding require more careful consideration of several factors such as ethnicity, gender, and the specific SE allele and genotype inherited. Large studies of heterogeneous groups of patients are required and indicate the need for collaborative efforts among researchers. In the interim, meta-analysis of the existing literature may provide some insight, because it allows utilization of the tremendous amount of research already completed. A preliminary meta-analysis highlighted the significant heterogeneity among the existing literature, and a more ambitious meta-analysis that uses individual patient-level data is currently ongoing. Profound implications exist for determination of the precise relationship between the SE and RA severity. This information could be valuable in identifying patients at greater risk of severe complications or as a stratification variable for clinical trials. Moreover, patients genetically predisposed to severe disease may benefit from early initiation of more aggressive therapy. Ultimately, clarification of the role of the SE may be valuable for the development of specific therapies directed toward DRB1 and related targets.