This chapter about antithrombotic therapy in native and prosthetic valvular heart 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 rheumatic mitral valve disease and atrial fibrillation (AF), or a history of previous systemic embolism, we recommend long-term oral anticoagulant (OAC) therapy (target international normalized ratio [INR], 2.5; range, 2.0 to 3.0) [Grade 1C+]. For patients with rheumatic mitral valve disease with AF or a history of systemic embolism who suffer systemic embolism while receiving OACs at a therapeutic INR, we recommend adding aspirin, 75 to 100 mg/d (Grade 1C). For those patients unable to take aspirin, we recommend adding dipyridamole, 400 mg/d, or clopidogrel (Grade 1C). In people with mitral valve prolapse (MVP) without history of systemic embolism, unexplained transient ischemic attacks (TIAs), or AF, we recommended against any antithrombotic therapy (Grade 1C). In patients with MVP and documented but unexplained TIAs, we recommend long-term aspirin therapy, 50 to 162 mg/d (Grade 1A). For all patients with mechanical prosthetic heart valves, we recommend vitamin K antagonists (Grade 1C+). For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, we recommend a target INR of 2.5 (range, 2.0 to 3.0) [Grade 1A]. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, we recommend a target INR of 3.0 (range, 2.5 to 3.5) [Grade 1C+]. For patients with caged ball or caged disk valves, we suggest a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/d (Grade 2A). For patients with bioprosthetic valves, we recommend vitamin K antagonists with a target INR of 2.5 (range, 2.0 to 3.0) for the first 3 months after valve insertion in the mitral position (Grade 1C+) and in the aortic position (Grade 2C). For patients with bioprosthetic valves who are in sinus rhythm and do not have AF, we recommend long-term (> 3 months) therapy with aspirin, 75 to 100 mg/d (Grade 1C+).