Infection with Epstein-Barr virus (EBV) and HLA-DRB1*1501-positivity is a risk factor for multiple sclerosis (MS), but whether an interaction between these two factors causes MS is unclear. We therefore conducted a meta-analysis on the effect of the interaction between HLA-DRB1*1501 and EBV infection on MS. Searches of PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and the Wanfan databases through February 2015 yielded 5 studies that met the criteria for inclusion in the meta-analysis. EBV infection and HLA-DRB1*1501-positivity were dichotomized. The additive (S) and multiplicative interaction indexes (OR) between EBV infection and HLA-DRB1*1501 and their 95% confidence intervals (95%CI) were calculated for each study and then combined in a meta-analysis. EBV infection was significantly associated with MS (OR = 2.60; 95%CI, 1.48-4.59). HLA-DRB1*1501 was associated with a significantly increased risk of MS (OR, 3.06; 95%CI, 2.30-4.08). An interaction effect between EBV infection and HLA-DRB1*1501 on MS was observed on the additive scale (S, 1.43; 95%CI, 1.05-1.95, P = 0.023), but no interaction effect was observed on the multiplicative scale (OR, 0.86, 95%CI, 0.59-1.26). This meta-analysis provides strong evidence that EBV alone, HLA-DRB1*1501 alone or their interaction is associated with an elevated risks of MS.