The use of cardiopulmonary bypass (CPB) is associated with the development of a significant systemic inflammatory response syndrome (SIRS) which can affect patient outcomes. Multiple pathways are involved in initiating and maintaining SIRS. We studied whether a single dose of steroids (dexamethasone) after the induction of anesthesia could blunt the SIRS from CPB. A prospective, randomized, double-blinded, placebo control trial of 28 patients (13 study vs. 15 control). The study group received 100 mg of dexamethasone whereas the control group received sterile saline. Inclusion criteria were the following: elective coronary artery bypass grafting, less than 80 years old, normal ejection fraction, no acute myocardial infarction. Serum levels of C3a, interleukin (IL)-6, and plasma norepinephrine (PNE) were measured after intubation, 30 minutes after initiation of CPB, 24 and 72 hours after termination of bypass. The study group demonstrated significantly lower levels of IL-6 (p = 0.0005) at 24 hours and PNE (p = 0.05) at 72 hours post-CPB. There were no differences in the C3a levels between the groups. No infections occurred in either group. A single dose of dexamethasone reduces IL-6 and PNE levels associated with CPB. Despite the significant reductions in IL-6 and PNE, there was no effect on clinical outcomes. Additional studies are needed to demonstrate a clinically significant effect on patient outcomes.