BACKGROUND Controversy exists regarding the optimal perfusion modality during cardiopulmonary bypass (CPB). Here we compare the effects of pulsatile versus nonpulsatile perfusion on microvascular blood flow during and after CPB. METHODS High-risk cardiac surgical patients were randomly assigned to have pulsatile (n=10) or nonpulsatile (n=10) flow during CPB. The sublingual microcirculation was assessed using orthogonal polarization spectral imaging. Hemodynamic and microvascular variables were obtained after anesthesia (baseline), during CPB, and post-CPB. RESULTS Compared with baseline, a normal microcirculatory blood flow pattern was accomplished at all time points under pulsatile flow conditions. Peaking 24 hours postoperatively, a higher proportion of normally perfused microvessels occurred under pulsatile versus nonpulsatile flow (56.0%±3.9% vs 33.3%±4.1%; p<0.05). Concurrently, pulsatility resulted in a reduction in the prevalence of pathologic hyper-dynamically perfused vessels (6.0%±3.4% vs 19.6%±8.8%; p<0.05). Leukocyte adherence decreased relative to the nonpulsatile group both during and after CPB. Furthermore, peak lactate levels were reduced under pulsatile flow conditions postoperatively. CONCLUSIONS Pulsatile perfusion is superior to nonpulsatile perfusion at preserving the microcirculation, which may reflect attenuation of the systemic inflammatory response during CPB. We suggest the implementation of pulsatile flow can better optimize microvascular perfusion, and may lead to improved patient outcomes in high-risk cardiac surgical procedures requiring prolonged CPB time.