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BACKGROUND This paper examines changes in substance use, and compares the resulting attributable burden of disease in the WHO European Region between 2010 and 2016. METHODS Data for 2010 and 2016 on the number of deaths, years of life lost (YLL) and disability-adjusted life years (DALYs) lost were obtained by sex and country from the 2016 Global Burden of Disease (GBD) study. Exposure data for all substances except alcohol were obtained from the same study, while alcohol data were obtained from the WHO. Proportional changes were calculated for the WHO European Region as a whole to identify trends and for sub-regions to identify which regions contributed most to trends. RESULTS In the WHO European Region in 2016, substance use caused 2.1 million deaths, 48.6 million YLL and 57.9 million DALYs lost, representing 22.4, 29.0 and 20.4% of all deaths, YLL and DALYs, respectively. The substance-attributable burden of disease was higher among men than women and highest in the eastern parts of the WHO European Region. Changes in the number of deaths, YLL and DALYs lost between 2010 and 2016 were almost uniformly downward, with the largest proportional changes observed for men. Exposure to tobacco, alcohol and illicit drugs also decreased uniformly. CONCLUSIONS Substance use and its attributable mortality and burden of disease have decreased in the WHO European Region since 2010. However, overall levels of substance use and the resulting burden of disease in the Region remain high compared with other regions of the world.