Background: Restless legs syndrome (RLS) is a sensory-motor disorder characterized by an uncomfortable sensation felt in the lower extremity. The aim of this systematic review and meta-analyses was (i) to provide updated information on the prevalence and clinical characteristics of RLS amongst people with multiple sclerosis (PwMS) and (ii) clarify RLS-related factors in PwMS. Methods: MEDLINE (PubMed), Scopus, and EMBASE were searched from their inception through April 2021 for the following keywords: 'restless legs syndrome' or 'RLS' and 'multiple sclerosis' or 'MS'. For the analysis of RLS prevalence, we calculated the percentage of RLS sufferers amongst the PwMS and people without MS. The prevalence of RLS was pooled separately for PwMS and healthy controls, regardless of the heterogeneity between studies. The odds ratios (ORs) and 95% CIs were extracted from the data in order to analyze the association between MS and RLS. Results: Nineteen studies were included in the review (9 case-controlled and 10 cross-sectional).The mean prevalence of RLS in the MS population was 27.5%, ranging from 13.2% to 65.1%, higher than the healthy controls. Based on the case control studies, the pooled RLS prevalence was much higher in PwMS than in healthy controls (OR 4.535, 95% CI 3.043-6.759, p<0.001). The majority of studies found no significant relationship between the presence of RLS in PwMS with disability, disease duration, type of MS, age, or gender. Conclusions: Our updated systematic review strengthens the evidence of the increased risk of RLS amongst PwMS. Nevertheless, significant data reporting on characteristics of the MS disease, which increases the risk of suffering from RLS, is still lacking.