Failure of anticoagulant therapy in a patient with a St. Jude heart valve in the mitral position is reported. After 8 years of optimal anticoagulation at an International Normalized Ratio between 2.5 and 3.5, a floating thrombus was discovered by chance during transthoracic echocardiography and then surgically removed. A study for congenital or acquired thrombophilia disclosed a positivity for activated protein C resistance, due to the presence of factor V Leiden. The intensity of warfarin anticoagulation was increased to provide more protection for the patient.