BACKGROUND: Comorbidities are common in multiple sclerosis (MS). The high prevalence of pain in MS is well-established but the influence of comorbidities on pain, specifically, pain-related interference in activity is not. OBJECTIVE: To examine the relationship between comorbidity and pain in MS. METHODS: We recruited 949 consecutive patients with definite MS from four Canadian centres. Participants completed the Health Utilities Index (HUI-Mark III) and a validated comorbidity questionnaire at 3 visits over 2 years. The HUI's pain scale was dichotomized into two groups: those with/without pain that disrupts normal activities. We used logistic regression to assess the association of pain with each comorbidity individually at baseline and over time. RESULTS: The incidence of disruptive pain over two years was 31.1 per 100 persons. Fibromyalgia, rheumatoid arthritis, irritable bowel syndrome, migraine, chronic lung disease, depression, anxiety, hypertension, and hypercholesterolemia were associated with disruptive pain (p<0.006). Individual-level effects on the presence of worsening pain were seen for chronic obstructive pulmonary disease (odds ratio [OR]: 1.50 95% CI: 1.08-2.09), anxiety (OR: 1.49 95% CI: 1.07-2.08), and autoimmune thyroid disease (OR: 1.40 95% CI: 1.00-1.97). CONCLUSION: Comorbidity is associated with pain in persons with MS. Closer examination of these associations may provide guidance for better management of this disabling symptom in MS. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.