Protein S is a vitamin K-dependent coagulation factor that acts as an anticoagulant. Deficiency of protein S increases the risk of thromboembolic events. We report a case of isolated protein S deficiency in a 39-year-old woman suffering arterial occlusion in both lower legs. She underwent a surgical procedure using thrombectomy and balloon angioplasty of her left lower extremity. Later, she had right trans-tibial amputation because of the reperfusion injury. Throughout the evaluation of thromboembolic events, we diagnosed a large thrombus in the right atrium and an asymptomatic pulmonary thromboembolism. The patient was successfully treated with right atrial thrombectomy and systemic anticoagulation. Careful evaluation for protein S levels may be necessary in patients with arterial thromboembolic events, especially young adults.