Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. COVID-19 has presented a significant challenge to the care providers of patients with MS. Objectives: The present study aimed to investigate the frequency of COVID-19 infection and its seropositivity in MS patients in Guilan, Iran, in 2021. Materials & Methods: In this analytical-cross-sectional study, all patients with relapsing-remitting MS registered in the Guilan MS Association with an expanded disability status scale of less than 5 who were referred for evaluation participated in the study. Information related to the clinical and serological symptoms of COVID-19 infection, changes in drug use, and the occurrence of new attacks were collected. Serological results of COVID-19 (IgG) among them were registered. Results: In total, 260 patients with MS (78.8% women, and 21.2% men) with a Mean±SD age of 38.7±9.9 years, and a Mean±SD duration of MS of 8.9±4.9 years were investigated. The most commonly used drugs were Dimethyl fumarate, Interferon, and Rituximab, respectively. Thirty-three patients (12.6%) had a clinical COVID-19 infection, of which 32 people had a mild and only one had a critical infection. Eight patients (1.3%) had positive COVID-19 IgG tests. No significant relationship was found between the COVID-19 infection with the type of medication, medication change, clinical attack of MS, and co-morbidities (P>0.05). Conclusion: A few patients had positive COVID-19 IgG tests and clinical COVID-19 infection. The vast majority had mild disease, and the clinical attack was not related to COVID-19 infection.