OBJECTIVES:  To understand dissimilarities in the inclusion and assessment of evidence in HTA decision-making process leading to different outcomes for Multiple Sclerosis treatments. METHODS: The collection and analysis of HTA data were based on an adjusted analytical framework developed and applied to evaluate and compare HTA evidence with application to other diseases. A set of 66 HTA reports were reviewed and the data collected qualitatively was quantitatively analysed with the software Nvivo10 to identify the influence of the criteria on the final outcomes and to measure the extent of differences across cases and how these contributed to explaining different outcomes. RESULTS: Eight countries (England, Scotland, Sweden, France, Germany, Italy, Canada, Australia) and ten DMT treatments (IFNβ 1a IM, Alemtuzumab, IFNβ 1a SC, Glatiramer acetate, Teriflunomide, Dimethyl fumarate Fingolimod, Natalizumab, two brand of IFNβ-1b and, Peginterferon beta-1a) were selected for the analysis. Across the 66 HTA reports identified, six out of 10 have completely opposite decision (DNL vs LWC-L). Our analysis showed a high level of heterogeneity across countries in appraising disease-modifying treatment for Multiple sclerosis, specifically in the assessment of the Health-related Quality of Life factors and in the economic evidence. In some cases, the inclusion and assessment of some of different evidence led clearly to a rejection or restriction decision. Different levels of involvement of stakeholders as well as other social values judgements influencing the decisions were identified. CONCLUSIONS: This research showed, through the application of a methodological approach, first, the heterogeneity across countries in appraising disease-modifying treatment for MS and, second, the need for a greater consistency in collecting economic and clinical data and evaluating the actual impact of MS.