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The experience of pain has been documented in small studies of individuals with multiple sclerosis (MS). The present study examines the prevalence of persistent pain and uncomfortable sensations among participants in the large North American Research Committee on MS (NARCOMS) Patient Registry. Registrants (10,176) responded to a questionnaire on pain and 7579 reported experiencing some level of pain during the month prior to the survey. Among the respondents 49% reported mild to severe pain and 49% of those indicated severe pain. Increased pain intensity was positively associated with gender (more women), multiple pain sites (51% of the severe pain group reported four or more pain sites), and constancy of pain (44% among the group with severe pain). There was also a positive association with increased MS-related disability, relapsing-worsening type of MS, and depression. Respondents with severe pain made greater use of the healthcare system and of prescribed analgesics, but were less likely to be satisfied with their doctors’ efforts to manage their pain. About one-third of the patients with moderate pain and 18% of those with severe pain reported no consultations for their pain. The effects of pain severity were fully evident in the respondents’ daily life, their work, mood, recreational activities and enjoyment of life. Our results indicate that the high prevalence of MS-related severe pain, low satisfaction with management of intense pain, and the perceived interference with quality of life indicators necessitate greater attention by healthcare providers to the management of pain and uncomfortable sensations in the MS population.