This is the second update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Patients, Interventions, Comparators, Outcomes) 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 methodology. The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of venous thromboembolism from initial management through secondary prevention and risk reduction of post-thrombotic syndrome. Four new guidance statements are added that did not appear in the 9th edition (2012) or first update (2016). Eight statements have been substantially modified from the first update. New evidence has emerged since 2016 which further informs the standard of care for patients with venous thromboembolism. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations.