This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously. We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update. New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations.