This chapter about antithrombotic therapy for venous thromboembolic disease is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this chapter are the following: for patients with objectively confirmed deep vein thrombosis (DVT), we recommend short-term treatment with subcutaneous (SC) low molecular weight heparin (LMWH) or, alternatively, IV unfractionated heparin (UFH) [both Grade 1A]. For patients with a high clinical suspicion of DVT, we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests (Grade 1C+). In acute DVT, we recommend initial treatment with LMWH or UFH for at least 5 days (Grade 1C), initiation of vitamin K antagonist (VKA) together with LMWH or UFH on the first treatment day, and discontinuation of heparin when the international normalized ratio (INR) is stable and > 2.0 (Grade 1A). For the duration and intensity of treatment for acute DVT of the leg, the recommendations include the following: for patients with a first episode of DVT secondary to a transient (reversible) risk factor, we recommend long-term treatment with a VKA for 3 months over treatment for shorter periods (Grade 1A). For patients with a first episode of idiopathic DVT, we recommend treatment with a VKA for at least 6 to 12 months (Grade 1A). We recommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations (Grade 1A). We recommend against high-intensity VKA therapy (INR range, 3.1 to 4.0) [Grade 1A] and against low-intensity therapy (INR range, 1.5 to 1.9) compared to INR range of 2.0 to 3.0 (Grade 1A). For the prevention of the postthrombotic syndrome, we recommend the use of an elastic compression stocking (Grade 1A). For patients with objectively confirmed nonmassive PE, we recommend acute treatment with SC LMWH or, alternatively, IV UFH (both Grade 1A). For most patients with pulmonary embolism (PE), we recommend clinicians not use systemic thrombolytic therapy (Grade 1A). For the duration and intensity of treatment for PE, the recommendations are similar to those for DVT.