TNFRSF6B and TNFRSF14 genes were recently associated with Crohn's disease and rheumatoid arthritis. TNFRSF14 is known as herpes virus entry mediator (HVEM), and herpes viruses have been involved in the aetiology of multiple sclerosis (MS). MS patients present human herpes virus 6 (HHV6) in active plaques and increased antibody responses to HHV6. We aimed to ascertain the role of these genes in MS susceptibility and to investigate the relationship of the gene encoding the widely expressed HVEM receptor with the active replication of HHV6 found in some MS patients. Genotyping of 1370 Spanish MS patients and 1715 ethnically matched controls was performed. HHV6A DNA levels (surrogate of active viral replication) were analysed in serum of MS patients during a 2-year follow-up. Both polymorphisms were associated with MS predisposition, with stronger effect in patients with HHV6 active replication-TNFRSF6B-rs4809330(*)A: P=0.028, OR=1.13; TNFRSF14-rs6684865(*)A: overall P=0.0008, OR=1.2; and HHV6-positive patients vs controls: P=0.017, OR=1.69.