OBJECTIVES: Multiple Sclerosis (MS) registries collect patient-level longitudinal data with the aim of improving our understanding of MS. These databases have provided extensive studies on the natural progression of MS. The purpose of this study is to assess how disease progression has been estimated and assess the consistency in methodology and results. METHODS: The publications of 10 major MS Registry websites were searched, followed up with keyword searches in Embase and Pubmed. Population-based natural history studies on disease progression were included. Primary and non-primary endpoints, such as Expanded Disability Status Scale (EDSS) outcomes as a measure of progression, were extracted in addition to statistical methodologies. We evaluated the consistency between studies in terms of endpoints and statistical methodology. RESULTS: Our search identified 23 studies, of which nine met the inclusion criteria. The majority of papers utilized the Kaplan-Meier Survival technique to estimate time until disease endpoints and Cox proportional hazard models to determine prognostic factors. Lack of standards in reporting results prevented a global comparison. The most commonly reported endpoint was median time to EDSS six for MS or relapsing-remitting MS patients, enabling comparison between six studies. Values were reported between 11.9 to 27.9 years. Excluding studies prior to 1999, the median time to EDSS six was between 20-27.9 years. Results reported from the European based Lyon and LORSEP registries were consistent (20-24 years), while studies in Canada and Germany showed greater disparity. Common prognostic factors included age and type of MS at onset. CONCLUSIONS: Lack of international standards for reporting outcomes in natural history progression hinders comparisons between studies, especially between the United States and Europe. While there is some consensus between registries regarding prognostic factors for progression, not all agree. Heterogeneity in underlying characteristics of the populations, evolution in best supportive care and access to treatments could all contribute.