Background: Recent studies suggest an association between rare variants in Mediterranean fever (MEFV), the gene underlying the auto-inflammatory disorder Familial Mediterranean Fever (FMF), the risk to develop multiple sclerosis (MS) and severity of MS. Objective: The objective of this study is to investigate these findings in a Belgian MS population and to test for association with additional clinical parameters such as treatment response. Methods: MEFV was sequenced in a cohort of MS patients ( N=94) suffering from auto-inflammatory symptoms, systemic side-effects upon interferon-beta (IFN-β) treatment, or patients in whom glatiramer acetate was started as first choice due to severe fatigue. Five rare non-synonymous variants were detected in this cohort and subsequently genotyped in 915 MS patients and 763 healthy controls. Results: We observed no association between these alleles and susceptibility to MS ( p-value=0.99) or disease severity ( p-value=0.78). However, we did observe a correlation between carrying an MEFV variant and the development of systemic side-effects upon IFN-β treatment ( p-value=0.022). Conclusion: In contrast to recent smaller studies, we did not find an association between carrying a rare variant in the MEFV gene and the risk to develop MS or disease severity. However, carrying rare variants in MEFV was associated with the development of severe systemic side-effects upon IFN-β treatment.