OBJECTIVES:  The Multiple Sclerosis International Quality of Life Questionnaire (MusiQoL) has been validated in paper and pencil form. Validating patient-reported outcomes using Item Response Theory (IRT) along with Classical Test Theory (CCT) methods are becoming progressively more common. The current study examined the psychometric properties of the MusiQoL among patients diagnosed with multiple sclerosis (MS) using an online version of the instrument. METHODS:  Data were used from a 2012 US survey of patients self-reporting a diagnosis of MS (N=1,000). The online survey collected information on patients’ demographics, disease and treatment history, and health outcomes.  Participants also completed the Multiple Sclerosis Rating Scale Revised (MSRS-R) and the abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9). Internal consistency and concurrent validity were examined for the domain-specific scores and the composite total score of the MusiQoL. IRT (one and two-parameter graded response models) analyses evaluated item discrimination and item difficulty. RESULTS: Among 1,000 patients with MS, 82.8% were female, the mean age was 48.7 (SD = 11.29), and 76.7% were currently using a disease-modifying medication. Internal consistency (Cronbach’s α) of the total scale of the MusiQoL was 0.913 and the domain scores ranged from 0.824 to 0.944. The total score of the MusiQoL were moderately-to-strongly correlated with MSRS-R (r=-0.551), and adequately correlated with the subscales of the TSQM-9 (r=0.138 to 0.348). Items varied in their discrimination (range: 1.507 to 4.814) and difficulty (range: -2.875 to 2.362) parameters. Majority of the MusiQoL domains best discriminated at lower levels of health-related quality of life (HRQoL). CONCLUSIONS: IRT and CCT are both helpful means for evaluating the psychometric properties of the MusiQoL. The MusiQoL in electronic form is reliable and valid for evaluating HRQoL in patients with MS, but performs best when discriminating among respondents with poorer HRQoL.