Interferon-beta (IFN-beta) is often discontinued in RRMS patients due to its most common side effect, the flu-like syndrome (FLS). The mechanisms underlying IFN beta-induced FLS symptoms are still unclear. The endocannabinoid system (ECS) is a key regulator of pain and inflammation. Thus we tested the hypothesis that the ECS could be involved in FLS severity by exploring the effect of genetic polymorphisms with functional impact on the ECS, on patient-reported FLS symptoms. GG-carriers of the transient-receptor-potential-vanilloid-1 (TRPV1) single nucleotide polymorphism rs222747 reported greater pain and weakness during FLS. This study suggests that the TRPV1 channel is involved in FLS severity. (C) 2017 Elsevier B.V. All rights reserved.