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Background Malaria causes more than 200 million cases of illness and 400,000 deaths each year across 90 countries. The World Health Organization (WHO) set a goal for 35 countries to eliminate malaria by 2030, with an intermediate milestone of 10 countries by 2020. In 2017, the WHO established the Elimination-2020 (E-2020) initiative to help countries achieve their malaria elimination goals and included 21 countries with the potential to eliminate malaria by 2020. Methods Across its three levels of activity (country, region and global), the WHO developed normative and implementation guidance on strategies and activities to eliminate malaria; provided technical support and subnational operational assistance; convened national malaria programme managers at three global meetings to share innovations and best practices; advised countries on strengthening their strategy to prevent re-establishment and preparing for WHO malaria certification; and contributed to maintaining momentum towards elimination through periodic evaluations, monitoring and oversight of progress in the E-2020 countries. Changes in the number of indigenous cases in E-2020 countries between 2016 and 2020 are reported, along with the number of countries that eliminated malaria and received WHO certification. Results The median number of indigenous cases in the E-2020 countries declined from 165.5 (interquartile range [IQR] 14.25–563.75) in 2016 to 78 (IQR 0–356) in 2020; 12 (57%) countries reported reductions in indigenous cases over that period, of which 7 (33%) interrupted malaria transmission and maintained a malaria-free status through 2020 and 4 (19%) were certified malaria-free by the WHO. Two countries experienced outbreaks of malaria in 2020 and 2021 attributed, in part, to the COVID-19 pandemic. Conclusions Although the E-2020 countries contributed to the achievement of the 2020 global elimination milestone, the initiative highlights the difficulties countries face to interrupt malaria transmission, even when numbers of cases are very low. The 2025 global elimination milestone is now approaching, and the lessons learned, experience gained, and updated guidance developed during the E-2020 initiative will help serve the countries seeking to eliminate malaria by 2025.

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