Isolated protein S deficiency is an inherited condition having proven association with venous thromboembolism. There is controversy regarding clear association between protein S deficiency and arterial thrombosis. It is therefore necessary to bring focus to this uncommon clinical condition and highlight the probable association with arterial thrombosis facilitating timely diagnosis of this condition. We describe a 48-year-old male with stroke and pulmonary thromboembolism with chronic deep vein thrombosis secondary to isolated protein S deficiency, managed with thrombolysis and long-term anticoagulation.