Cardiopulmonary bypass (CPB) alters systemic hemodynamics and affects several biochemical systems in cardiovascular regulation. We investigated the changes in levels of circulating epinephrine (E) and norepinephrine (NE) and related them to events during CPB. Twenty-eight patients undergoing various surgical procedures were studied. Plasma E and NE were determined by radioenzymatic assay at eight stages of the operation. A 9-fold increase in arterial E (from 75 ± 13 to 708 ± 117.3 pg/ml) occurred from prebypass (stage 1) measurements to the end of aortic cross-clamping (stage 4). The values at stage 4 were significantly higher (p < 0.05) than at all other stages. E decreased rapidly, to 360 ± 84.3 pg/ml, after myocardial and pulmonary reperfusion (stage 5). Arterial NE increased 2-fold from stage 1 to stage 4 (from 426 ± 66.9 to 825 ± 84.2, p < 0.05). The increase in NE from initial CPB values (stage 2) to 30 minutes of aortic cross-clamping (stage 3) was associated with an increase in mean blood pressure (r = 0.51, p = 0.02). The peak increases in catecholamines occurred when the heart and lungs were excluded from the circulation, which suggests that either or both contributed to the increase. Because the increase in E was markedly greater than that in NE, the predominant humoral response to CPB appears to be adrenomedullary release of E. This significant increase in catecholamines could jeopardize myocardial protective measures during CPB.