The aim of this work was to identify common HLA Class II alleles contributing to primary Sjögren's syndrome (pSS) susceptibility worldwide and to analyze their biological implications through a binding prediction approach of peptides from major pSS auto-antigens. Case-control studies on HLA-DQ and HLA-DR in pSS were searched in various literature databases through April 2011 by a systematic review. The effect summary odds ratios and 95% confidence intervals were obtained by means of the random effect model. A total of 1166 cases and 6470 controls from 23 studies were analyzed. At the allelic level, DQA1 *05:01, DQB1 *02:01, and DRB1 *03:01 alleles were found to be risk factors for disease. Conversely, the DQA1 *02:01, DQA1 *03:01 and DQB1 *05:01 alleles were protective factors. The current study stresses the significant size effect HLA exhibits in the development of pSS. Analysis of susceptibility and protective alleles revealed physicochemical differences in critical amino acids located within the antigen-binding groove of DR?, DQ? and DQ? chains, allowing us to infer a mechanistic approach to understand the role of HLA in pSS and other autoimmune diseases. © 2011 Elsevier B.V.