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Background: Restless legs syndrome (RLS) frequency, and its association with depression, anxiety, sleep disorders, and fatigue, has not been previously studied in Latin American patients with multiple sclerosis (MS). We aimed to assess RLS frequency in patients with MS living in Argentina and to examine potential associations with depression, anxiety, and sleep disorders., Methods: A cross-sectional study (n = 427) was conducted using a self-administered questionnaire, including International RLS Study Group criteria, to compare RLS frequency in patients with MS versus controls. The Hospital Anxiety and Depression Scale and the Fatigue Severity Scale were administered to all participants. Insomnia, excessive daytime somnolence, and other risk factors in patients with MS with RLS were analyzed using logistic regression., Results: We included 189 patients with definite MS and 238 controls. The RLS frequency was 29.1% in patients with MS versus 13.0% in controls (odds ratio [OR] = 2.74, P = .00005). Moreover, clinically significant RLS (csRLS; ie, symptoms present ≥2 days per week) frequency was 19.4% in patients with MS versus 4.2% in controls (OR = 5.37, P < .00001). Longer MS duration and presence of anxiety, depression, insomnia, and smoking cigarettes were all significantly associated with RLS. Multivariate analysis showed that anxiety and fatigue were significantly associated with MS with RLS and MS with csRLS., Conclusions: Both RLS and csRLS showed strong association with MS, supporting the need to screen for anxiety/depression, sleep quality, and fatigue in this patient population. We believe that identifying the presence and severity of these conditions would contribute to better MS management and treatment., Competing Interests: The authors declare no conflicts of interest.