In 47 patients undergoing open-heart surgical procedures, the influence of cardiopulmonary bypass (CPB) on lymphocyte function was investigated by studying in vitro the mitogen responses of lymphocytes in whole blood cultures. Subnormal mitogen responses before operation that likely resulted from dexamethasone medication were found in half of the patients studied. During operation, changes in phytohemagglutinin responses were uniform in a group of 23 patients. No significant effect of anesthesia and operation was observed until the patients were heparinized (i.e., before CPB). At the end of operation, the phytohemagglutinin response was below normal. In a group of 24 other patients, postoperative mitogen responses were studied. A tendency toward restoration of mitogen responses was observed in most patients the first morning after operation. However, no uniform pattern of normalization of mitogen responses was found. In an attempt to relate postoperative mitogen responses to trauma resulting from CPB, we observed that perioperative (in comparison with postoperative) administration of blood coincided with a significantly higher incidence of subnormal phytohemagglutinin and pokeweed mitogen responses on postoperative day 1. No correlation between laboratory data and clinical findings could be established.