We have described three cases of pulmonary artery hypertension (PAH). Two of them developed severe systemic hypotension and cardiac arrest following cardiopulmonary bypass (CPB). Imminent pre-operative right ventricular (RV) failure and subsequent myocardial injury during CPB may have contributed to the insult following CPB. In these cases, RV failure is presumably due to rapid volume overloading, since left atrial pressure (LAP) was essentially unchanged while right atrial pressure (RAP) was markedly elevated during the period of severe hypotension. Furthermore, these events may be attributed to protamine, since the circulatory derangement coincides with its administration. Thus, in these patients with severe PAH, blood transfusion should be carefully titrated under the strict evaluation of both LAP and RAP. Additionally, protamine should be infused at a rate slow enough to avoid concomitant hemodynamic changes. We have also reported a case of over-systemic PAH who was successfully managed intraoperatively by careful monitoring and discreet administration of protamine.