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The 2019 Global Health Security Index concluded that although “no country is fully prepared for epidemics or pandemics,” the United States scored highest among all countries in pandemic preparedness. Yet in the COVID-19 outbreak as of October 2021, measured in deaths per 100,000 population, the United States did worse than 30 of the 35 countries defined by the International Monetary Fund as having “advanced economies,” and worse than all but 18 of 184 countries ranked. Many have now called for a US COVID-19 commission to provide a definitive reference for the history of the events, to enlarge the public’s understanding of them, and to prescribe strategies that might prevent, or at least mitigate, future pandemics. Drawing on our experience as members of the President’s Council of Advisors on Science and Technology (PCAST) under President Obama, we present recommendations for the topics to be examined by a US COVID-19 commission.