Regional myocardial acidosis, as measured with tissue pH electrodes during cardiac surgery, has been shown to be reflective of regional myocardial ischemia. This study examined the relationship between intraoperative regional myocardial acidosis and long-term survival of patients undergoing cardiac surgery with cardiopulmonary bypass. A total of 496 adult patients who underwent valve replacement, coronary artery revascularization, or both with intraoperative myocardial pH monitoring in the anterior and posterior left ventricular walls were followed up for 3 to 17 years (average 10.2 ± 4.9 years) for all cause mortality. Regional myocardial acidosis in each patient was defined by the lower of the anterior and posterior wall pH values. A bivariate automatic interaction detection analysis identified three significant regional myocardial acidosis thresholds that affected long-term mortality: pH 37C less than 6.63 before aortic crossclamping, integrated mean pH37C less than 6.34 during the period of aortic crossclamping, and pH37C less than 6.73 at discontinuation of cardiopulmonary bypass. Cox proportional hazard regression analysis identified each of these thresholds to be independently determinant of survival, with pH37C during aortic crossclamping having the highest risk ratio (risk ratio 2.15, 95% confidence interval 1.37-3.37). Raising pH37C from lower than threshold before aortic crossclamping to higher than threshold during clamping increased the median survival by 40.2%. In adult patients undergoing cardiac surgery with cardiopulmonary bypass, regional myocardial ischemic acidosis before aortic crossclamping, during aortic crossclamping, and at discontinuation of cardiopulmonary bypass are independently associated with reduced long-term postoperative survival. Reversing or avoiding myocardial acidosis during cardiac surgery improves long-term patient survival.