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• An increase in mortality for MS was observed especially for females. • Differences in mortality were observed between Italian geographical areas. • Mortality reflects prevalence and incidence trend. The epidemiology of Multiple Sclerosis (MS) is relevant for health-services planning. Most of MS prevalence and incidence studies in Italy referred to specific geographical areas and periods, whereas mortality data are routinely collected at the national level. The aim was to assess MS mortality trend and geographical differences in Italy from 1980 to 2015. Mortality data were provided by the Italian Institute of Statistics. Due to a low number of annual deaths, mortality data were analysed for both the entire period under study and for sub-periods. Temporal trends were first evaluated using age-adjusted mortality rates (AMRs) comparing each sub-period with the initial one. Then, the annual percent change in mortality was estimated through the joinpoint regression model. Spatial differences between 5 main geographical areas were evaluated using standardized mortality ratios (SMRs). During the study period, 4,959 deaths for males and 7,434 for females were observed. The higher overall AMR was observed for females (F:0.71 vs. M: 0.56 per 100,000 persons per year). Analysing mortality by gender and geographical area, SMRs 〈 100 were observed in South Italy for both sexes, and in Central Italy for males only, whereas SMRs 〉 100 for Islands for both sexes, and in North-East and North-West for females only. The analysis of the mortality trend through AMRs calculated for sub-periods revealed no difference between the first and the last period for males, whereas a significant increase in mortality was observed for females. The joinpoint regression analysis showed a significant decrease in mortality up to 1995 for males (APC -3.23%) and up to 1999 for females, (APC -1.01%), followed by a significant increase for both sexes, but more marked for females (APC +1.9% M, +2.34% F). The increasing trend of mortality for MS, especially for females, may reflect the increase in the prevalence of MS and the improvement in the quality of diagnosis or coding of the cause of death. [ABSTRACT FROM AUTHOR]