Current dosing practices for warfarin are empiric and result in the need for frequent dose changes as the International Normalized Ratio (INR) gets too high or too low. As a result, patients are put at increased risk of thromboembolism, bleeding, and premature discontinuation of a highly efficacious therapy. Also, primarily because of difficulties using the drug, there is substantial underuse of warfarin in millions of patients who would benefit from anticoagulation (AC). There is clearly a need to improve warfarin management. Although clinical research has identified clinical and genetic factors that can alter warfarin dose requirements, limited prospective, clinical research has examined the utility of using clinical and genetic information to improve outcomes among a large, diverse group of patients using warfarin. The objective of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial is to conduct a multicenter, double-blind, randomized trial comparing two approaches to guiding warfarin therapy initiation: 1) initiation of warfarin therapy based on algorithms using clinical information and an individual's genotype using genes known to influence warfarin response ([unreadable]genotype-guided dosing[unreadable]), and 2) initiation of warfarin therapy based on algorithms using only clinical information ([unreadable]clinical-guided dosing[unreadable]). The study hypothesis is that the use of genetic and clinical information for selecting the dose of warfarin during the initial dosing period will lead to improvement in stability of AC relative to a strategy that incorporates only clinical information (without genetics) for initial dosing. Each study arm will include a baseline dose initiation algorithm and a dose revision algorithm applied over the first 4 to 5 doses of warfarin therapy. By comparing the two strategies in this trial, the study will be able to determine if genetic information provides added benefit above and beyond what can be done simply with clinical information.