Background: We previously demonstrated that a dose of glucocorticoids (GCs) administered prior to cardiopulmonary bypass (CPB) is effective at suppressing the inflammatory response to CPB and leads to an improved postoperative course. We evaluated whether an additional dose of GC administered eight hours prior to CPB would lead to further clinical benefit. Methods: We conducted a prospective study in which patients were randomized to receive placebo or GC eight hours prior to CPB, in addition to a dose of GC administered following induction of anesthesia. We measured serum inflammatory mediator levels and postoperative clinical parameters. Results: Thirty-one patients were included in the study. Eighteen patients received two doses of GC and 13 patients received a single does of GC. Complement C3a levels were significantly lower at 24 hours following surgery in those patients who received two doses of GC (3136 +/- 1650 vs 1779 +/- 1616 ng/mL, P = .04). There was no significant difference in tumor necrosis factor (TNF)-alpha or interleukin (IL)-6 levels at any time between groups. There was no significant difference in core body temperature or renal function (based on serum creatinine levels) between groups. There was no significant difference between groups in duration of mechanical ventilation (2.4 +/- 1.5 vs 3.6 +/- 3.7 days, two vs one dose, respectively, P = .33) or length of stay in the intensive care unit ([ICU]; 3.4 +/- 1.4 vs 4.9 +/- 3.6 days, 2 vs 1 dose, respectively, P = .15). Conclusion: While those patients who received two doses of GC prior to surgery had significantly less complement activation postoperatively, clinical outcomes did not differ between groups. We conclude that the practice of administering an additional dose of GC prior to CPB is not supported. However, a large randomized study is needed to conclusively discount the potential benefit of this strategy.