Multiple sclerosis (MS) being a progressive neurological disease with no cure, lends itself as an important area for health-related quality of life (HRQOL) research. A number of questionnaires have been designed to measure HRQOL in MS patients, but no one measure has been established as a gold standard. The large number of questionnaires also gives neurologists a range of choices but limited information on which to base their selection. In order to determine the relative advantages and disadvantages of the HRQOL questionnaires, a comparison of their psychometric properties in the same patient population is necessary. OBJECTIVE: To review the current literature and identify studies comparing psychometric properties of MS-related QOL measures within the same patient population. METHODS: Studies included were those that administered more than one HRQOL questionnaire in the same group of patients with MS. The search was restricted to the PUBMED and MEDLINE databases for articles published between 1991 and 2005. RESULTS: Of almost 30 MS-related QOL questionnaires, psychometric properties for only 8 have been compared in 4 different published studies. A common comparator in all four studies has been the Medical Outcomes Survey Short Form (SF-36). Responsiveness to change and patient preferences regarding the questionnaires have been compared less frequently. Overall, the Multiple Sclerosis Impact Scale (MSIS-29) has been shown to perform better over a range of psychometric properties compared to the commonly used MSQOL and the Functional Assessment in MS (FAMS). CONCLUSIONS: MSIS-29 appears to be a psychometrically sound measure of QOL in MS. However, owing to the paucity of psychometric comparisons in the MS literature, further rigorous head-to-head comparisons of newer as well as existing questionnaires with MSIS-29 are warranted. Such results can guide researchers in selecting an appropriate measure for use in clinical trials as well as routine clinical practice.