Key PointsQuestionWhat is the effect of P2Y12 inhibition, a proposed therapeutic target and preventive strategy, on clinical outcomes in critically ill patients hospitalized for COVID-19?FindingsIn this randomized clinical trial that included 949 participants, use of a P2Y12 inhibitor did not result in a greater number of days alive and free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization.MeaningThese data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.