Protein S (PS) along with activated protein C plays an important role in the down-regulation of in vivo thrombin generation. Its deficiency can cause abnormal and inappropriate clot formation within the circulation necessitating chronic anticoagulation therapy. The risk of developing thrombotic complications is heightened in the perioperative period in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Heparin resistance is very rare in these patients, especially when antithrombin levels are near normal. Management of CPB in this scenario is quite challenging. We report the perioperative management, particularly the CPB management, of a patient with type I PS deficiency and incidentally detected heparin resistance, who underwent coronary artery bypass grafting with CPB.