Venous thromboembolism (VTE) results from the interaction of the Virchow triad (venous stasis, endothelial injury, and hypercoagulability). Risk factors for increased hypercoagulability, or thrombophilia, include activated protein C resistance/factor V Leiden, the prothrombin G20210A mutation, deficiencies of the natural anticoagulants (antithrombin, proteins C and S), antiphospholipid antibodies, hyperhomocysteinemia, and increased factor VIII activity. Not all patients with VTE need to be tested for such risk factors, but patients with thrombophilia should be evaluated for all possibilities to better estimate risk. At the same time, testing should be patient-specific because assay results are affected by preanalytic variables, including thrombosis and anticoagulant therapy. Copyright© by the American Society for Clinical Pathology.