We sought to establish the efficacy and safety of prophylactic steroids in adult patients undergoing cardiopulmonary bypass (CPB). We performed a meta-analysis of randomized trials reporting the effects of prophylactic steroids on clinical outcomes after CPB. Outcomes examined were mortality, myocardial infarction, neurological events, new onset atrial fibrillation, transfusion requirements, postoperative bleeding, duration of ventilation, intensive care unit (ICU) stay, hospital stay, wound complications, gastrointestinal complications, and infectious complications. We included 44 trials randomizing 3205 patients. Steroids reduced new onset atrial fibrillation [relative risk (RR) 0.71, 95% confidence interval (CI) 0.59 to 0.87], postoperative bleeding [weighted mean difference (WMD) -99.6 mL, 95% CI -149.8 to -49.3], and duration of ICU stay (WMD -0.23 days, 95% CI -0.40 to -0.07). Length of hospital stay was also reduced (WMD -0.59 days, 95% CI -1.17 to -0.02), but this result was less robust. A trend towards reduction in mortality was observed (RR 0.73, 95% CI 0.45 to 1.18). Randomized trials suggest that perioperative steroids have significant clinical benefit in CPB patients by decreasing the risk of new onset atrial fibrillation, while results are encouraging for reducing bleeding, length of stay, and mortality. These data do not raise major safety concerns, however, a sufficiently powered trial is warranted to confirm or refute these findings.