Background: As remote infections with common herpes viruses are associated with modulation of the risk of multiple sclerosis (MS), we hypothesized that antibody concentrations against these viruses may further modify risk. As many common viruses are first encountered during childhood, pediatric MS offer a unique opportunity to investigate more closely their influence on susceptibility. Our aim was to determine if MS patients who were positive for these viruses had higher levels of antibodies to these viruses. We also assessed whether human leukocyte antigen (HLA)-DRB1*1501 genotype influenced viral antibody levels. Methods: Antibody response levels toward Epstein Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV)-1, and HLA-DRB1*1501 status were determined in pediatric MS patients (n=189) and controls (n=38). Multivariate analyses were used, adjusted for age, gender, race, ethnicity and use of disease-modifying therapies. Results: The antibody concentrations against EBV (Epstein-Barr nuclear antigen 1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA)), CMV and HSV-1 were similar between pediatric MS patients and controls positive for seroconversion against the virus of interest. EBNA-1 humoral responses were higher in HLA-DRB1 positive individuals (p=0.005) whereas other viral humoral responses were similar in HLA-DRB1 positive and negative individuals. Conclusion: Among those positive for EBNA-1, MS patients did not have higher levels of antibody response to EBNA- 1: however, titers for EBNA-1 were higher in those who were HLA-DRB1 positive. This suggests that genotype might influence the humoral response to EBV. Whether other genotypes influence antibody response to other viruses remains to be determined. © The Author(s) 2012.