Background: Tumefactive multiple sclerosis (TMS) is a rare variant of multiple sclerosis presenting with large inflammatory lesions that can mimic tumors or other space-occupying lesions. There is a scarcity of data on the epidemiology of TMS. Objectives: We aimed to report incidence rate, clinical and radiological features of TMS in Olmsted County, Minnesota. Methods: All residents of Olmsted County, Minnesota, diagnosed with TMS from January 1 1998 to December 31 2018 were identified using the Rochester Epidemiology Project database. Incidence rates were directly adjusted by age and sex to the 2010 US total population. Results: Out of 792 patients with multiple sclerosis, 14 patients (8 males, 6 females) had TMS representing 1.8% of the MS population. The median age at attack onset was 38.1 years (range 20-61). The tumefactive lesion was the first clinical MS attack in 6/14 MS patients. Of the 10 patients with CSF analysis, CSF Oligoclonal bands (OCBs) were present in 8/10 patients. Barkhof criteria for dissemination in space was met in 10/14 patients. Most patients remained fully ambulatory (Expanded Disability Status Scale (EDSS) ? 4 in 11/14 (78%)) with a relapsing- remitting course after median of 8 years of follow-up. The overall age-adjusted annual incidence rates was 0.7/100,000 [95% CI: 0.33-1.07 and when age- and sex adjusted to the 2010 US total population the overall annual incidence rate was 0.71 [95% CI: 0.34-1.08]. Conclusions: In a well-defined North American population, TMS incidence appears to be rare with favorable clinical outcome.