Objective: Evaluate the prevalence and costs of co-morbidities in employees with/without multiple sclerosis (MS). Methods: A United States employee health care claims database from 2001-2007 was used to identify subjects with MS (ICD-9 code=340.XX) and a control cohort without MS. The control group was matched 20:1 to the MS subjects on demographics, job-information, geography, and Charlson Co-morbidity Index. Based on ICD-9 codes, direct medical costs associated with the Agency for Health care Research and Quality 17 Major and 261 Specific Diagnostic Categories (MDCs and SCs) were identified. Index dates for the MS cohort were the diagnosis or therapy initiation date, and for Controls the average MS date. The 12-month post-index date utilization and costs were analyzed. Prevalence comparisons were tested using z-scores of log odds ratios and cohort cost comparisons using t-tests (P<0.05). Results: A total of 765 employees with MS and 15,300 matched controls were analyzed. The MS cohort had significantly higher prevalence of 15/17 MDCs and were significantly costlier in 7. The top more prevalent MDCs were: Nervous System+Sense Organs, Musculo Connective Tissue, and “Other Conditions” which had 53.4%, 18.2% and 17.1% higher prevalence, respectively and were $1837, $256, and $241 more costly, respectively. However, it was surprising to see the prevalence and higher cost of conditions like: Circulatory System (31.1%–21.9%; $568–$235) Mental Disorders (20.7%–11.6%; $147–$61) Digestive System (23.9%–16.2%; $369–$193); Skin & Subcutaneous Tissue (25.4%–19.7%; $129–$69). Evaluating these using the “specific categories”, significantly higher prevalence and costs were reported among the MS cohort in: other nervous system disorders, headache and migraine, epilepsy convulsions, blindness and vision defects, dizziness/vertigo, other mental conditions. Conclusion: Employees with MS have more prevalent co-morbid conditions than subjects without MS. From an insurer's perspective, this increased burden for MS sufferers is also associated with higher costs.