OBJECTIVES: To evaluate the United States health-related quality-of-life burden of multiple sclerosis (MS) as compared to other debilitating chronic conditions using nationally representative data from the Medical Expenditure Panel Survey (MEPS). METHODS: We identified a sample of non-institutionalized patients aged ≥18 with MS (ICD-9 code 340) using MEPS data (1998-2009) and compared them to individuals without MS.  Similarly, cohorts were generated for the following common debilitating chronic conditions and their respective non-condition control cohorts: rheumatoid arthritis (ICD-9 code 714.0), diabetes (ICD-9 code 250.0 – 250.93), inflammatory bowel disease (ICD-9 code 555), depressive disorder (ICD-9 code 311), acute coronary syndrome (ICD-9 code 411.1), and asthma (ICD-9 code 493).  The incremental changes for condition versus control were estimated for the 12-item Short Form Health Survey (SF-12) physical and mental summary scores, and the SF-6D, a preference (utility) measurement adaptation of the Short Form-36 questionnaire.  We used ordinary least squares regression (separate model for each chronic condition versus control comparison) and included adjustment for gender, race, ethnicity, region, age, insurance status, education, number of chronic conditions other than the analyzed chronic condition, and survey year. RESULTS: As compared to other debilitating chronic conditions, the adjusted decrement in the SF-12 physical summary score was highest for MS (-11.89), followed by rheumatoid arthritis (-7.23), and inflammatory bowel disease (-3.94). The adjusted decrement in the SF-12 mental summary score for MS was (-2.9), second only to depression (-8.9). The adjusted SF-6D preference score deduction was highest for MS (-0.11), followed by depression (-0.10) and rheumatoid arthritis (-0.07).  The p-values were <0.05 for all listed decrements compared to the control cohorts. CONCLUSIONS: MS is associated with the lowest HRQoL compared to other debilitating chronic conditions, with the exception of depression on the SF-12 metal summary score, demonstrating the extreme burden this disease places on the patient and society.