OBJECTIVE: To validate the newly developed Multiple Sclerosis Impact Scale (MSIS-29) in a large, well characterized, independent group of MS patients by investigating the relation between the MSIS-29 and the Guy's Neurological Disability Scale (GNDS), the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). METHODS: Two hundred MS patients were recruited at our outpatient department. At the same visit GNDS, EDSS, MSFC and MSIS-29 were assessed. Data obtained from GNDS, EDSS and MSFC assessment were compared to both physical and psychological impact scores of the MSIS-29. In addition the contribution of GNDS subcategories, EDSS functional systems and MSFC components to the physical and psychological impact scores of the MSIS-29 was studied. RESULTS: Median scores were 37.5 for the physical and 22.2 for the psychological impact score of the MSIS-29, 13.0 for GNDS and 4.0 for EDSS. Mean MSFC was 0.07. The physical impact score showed good correlations with both GNDS (0.79) and EDSS (0.68) and a moderate correlation with the MSFC (-0.53). The psychological impact score showed weak correlations with EDSS (0.22) and MSFC (-0.30) and a moderately strong correlation with the GNDS (0.58). In 50 (25%) patients, scores on physical and psychological impact scales diverted, i.e., a relative high score on one scale combined with a relative low score on the other scale. This was related to the clinical disease course. CONCLUSION: Our study supports the use of the MSIS-29 as a measure for the assessment of physical impact of MS on normal daily life. In addition, our data provides a deeper understanding of the factors that determine both physical and psychological disease impact. Discrepancies between the latter two aspects deserve further attention.