Background: The five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) is a preference-based measure of health-related quality of life (HRQOL), which yields an index score anchored at 0 (dead) and 1 (full health). We lack evidence on estimates for the minimally important difference (MID) of the EQ-5D-5L that will help in interpreting differences or changes in HRQOL measured by this scale score. Objectives: To estimate the MID of the EQ-5D-5L index score for available scoring algorithms including algorithms from Canada, China, Spain, Japan, England, and Uruguay. Methods: A simulation based approach based on instrument-defined single-level transitions was used to estimate the MID values of the EQ-5D-5L for each country-specific scoring algorithm. Results: The simulation-based instrument-defined MID estimates (mean +/- SD) for each country specific scoring algorithm were as follows: Canada, 0.056 +/- 0.011; China, 0.069 +/- 0.007; Spain, 0.061 +/- 0.008; Japan, 0.048 +/- 0.004; England, 0.063 +/- 0.013; and Uruguay, 0.063 +/- 0.019. Differences in MID estimates reflect differences in population preferences, in valuation techniques used, as well as in modeling strategies. After excluding the maximum-valued scoring parameters, the MID estimates (mean +/- SD) were as follows: Canada, 0.037 +/- 0.001; China, 0.058 +/- 0.005; Spain, 0.045 +/- 0.009; Japan, 0.044 +/- 0.004; England, 0.037 +/- 0.008; and Uruguay, 0.040 +/- 0.010. Conclusions: Simulation-based estimates of the MID of the EQ-5D-5L index score were generally between 0.037 and 0.069, which are similar to the MID estimates of other preference-based HRQOL measures. Copyright (C) 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.