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Cardiopulmonary bypass (CPB) induces a systemic inflammatory response characterized by release of proinflammatory cytokines, including interleukin 6 (IL-6). Recent reports suggest that plasma IL-6 is increased after CPB. Previous studies evaluating the influence of duration of CPB and/or aortic cross-clamp time on the release of IL-6 are conflicting. Infusion of blood and blood products during these studies may have influenced plasma concentrations of proinflammatory cytokines by inducing host cell (monocyte) activation and IL-6 release. The purpose of our investigation was to determine, in an environment free from blood and/or blood product administration, the influence of duration of CPB and/or aortic cross-clamp on the magnitude of the IL-6 response in patients undergoing cardiac surgery. We prospectively evaluated plasma IL-6 levels preinduction (T0) and at sternal closure in 16 patients undergoing CPB (coronary artery bypass grafting, n = 9; valvular cardiac surgery, n = 7) to determine whether there is a correlation between the absolute increase in IL-6 and the duration of CPB or aortic cross-clamp time. None of the patients received blood and/or blood products during the study to control for the introduction of additional activated cells and soluble mediators, including IL-6. The results demonstrate that the magnitude of the IL-6 response to CPB is positively correlated with the duration of CPB but not with duration of aortic cross-clamp. It seems that induction of IL-6 release is part of a normal response to CPB and does not depend on activation of host cells during prolonged aortic cross-clamp. The activation or presence of inflammatory cytokines associated with administration of blood and/or blood products could have influenced previously published investigations relating the influence of duration of CPB and/or aortic cross-clamp time to the magnitude of the IL-6 response. Implications: This study found a positive correlation between the magnitude of the interleukin 6 response to cardiopulmonary bypass and duration of cardiopulmonary bypass (but not duration of aortic cross-clamp) when measurements were made in the absence of blood/blood product transfusion. Future studies evaluating strategies to reduce cytokine responses to cardiopulmonary bypass should therefore control for cardiopulmonary bypass duration.