This systematic review and meta-analysis explores the clinical efficacy of biocompatible surfaces for cardiopulmonary bypass in adults. Thirty-six randomized controlled trials were retrieved for a total of 4360 patients. Patients treated with biocompatible circuits had a lower rate of packed red cells transfusions and atrial fibrillation, and shorter durations of stay in the intensive care unit. When the analysis was limited to high-quality studies, only a reduction in atrial fibrillation rate and a shorter stay in the intensive care unit remained significantly associated with the use of biocompatible surfaces. Using biocompatible surfaces without other measures to contain blood activation results in a limited clinical benefit.