Objective: To identify the contribution of HLA-DRB1 alleles to susceptibility or resistance to multiple sclerosis (MS) in Caucasians through a meta-analysis of non-family-based studies. Methods: A systematic review of case-control studies in Caucasians was performed. Studies examining allele or phenotype frequencies were analyzed separately. Odds ratio (OR) and 95% confidence intervals (Os) were used. We also used the relatively predispositional effect (RPE) method to analyze several allele frequency studies to avoid skewed results due to some strongly associated alleles. Results: A total of 5464 cases and 7809 controls from 14 allele frequency studies and a total of 5401 cases and 7538 controls from 23 phenotype frequency studies were analyzed. DRB1*15 was definitely the strongest risk factor for MS (allele group, Pc<0.00013, OR 2.59, 95%CI 2.34-2.87; phenotype group, Pc<0.00013, OR 3.35, 95%CI 2.95-3.80). DRB1*03 frequencies were significantly increased among MS cases in the phenotype group (Pc = 0.0013, OR 1.21, 95%CI 1.09-1.33) but not in the allele group. DRB1*14 and DRB1*07 showed protective effects against MS in both groups (DRB1*14, allele group, Pc<0.00013, OR 0.53, 95%CI 0.42-0.66; phenotype group, Pc<0.00013, OR 0.57, 95%CI 0.45-0.71; DRB1*07, allele group. Pc<0.0026. OR 0.75, 95%CI 0.64-0.87; phenotype group, Pc<0.00013, OR 0.67, 95%CI 0.61-0.73). By RPE method, DRB1*14, and DRB1*07 showed protective effects after excluding DRB1*15 from the analysis. DRB1*03 was significantly higher in MS cases than controls after removing both DRB1*15 and DRB1*14. Conclusions: In Caucasians, we highlighted the definite protective role of HLA-DRB1*14 and DRB1*07 for MS. DRB1*03 is probably the only risk factor for MS besides DRB1*15 and a common genetic foundation for autoimmune disease. Targeting to these alleles may have potential values in prevention or therapy for MS in the specific population. (C) 2011 Elsevier B.V. All rights reserved.