Protein S deficiency is a form of thrombophilia in which the anticoagulant protein S is underproduced or not produced at all by the body. Lifelong anticoagulation is the mainstay of treatment. Transcatheter aortic valve replacement (TAVR) is a current treatment modality for patients with severe aortic stenosis. We are reporting the case of a patient with this disease who underwent a TAVR procedure and experienced valve leaflet thrombosis and large arterial thrombosis in the following months while fully anticoagulated with typical anticoagulation methods including warfarin, apixaban, and enoxaparin. Literature-based guidance is lacking with regard to anticoagulation in the setting of TAVR patients, especially in those with protein S deficiency. Based on our observations, warfarin was the better long-term prophylactic management method for our patient’s protein S deficiency. Enoxaparin was most useful during periods of elevated thrombosis risk, including intra-/post-operative care and prolonged hospitalization periods. In the setting of her TAVR, we observed that warfarin use with a target international normalized ratio (INR) of 2.5-3.5 was the most effective outpatient treatment for the reversal of thrombosed bioprosthetic valve and improvement of cardiac ejection fraction. It is also possible that initial post-operative warfarin use would have been the most effective means of preventing valve thrombosis entirely in our protein S-deficient patient.