Minimally invasive extracorporeal perfusion technologies are based on the use of a minimally invasive extracorporeal circulation (MiECC) system. This includes a closed CPB circuit; biologically inert blood contact surfaces; reduced priming volume; a centrifugal pump; a membrane oxygenator; a heat exchanger; a cardioplegia system; a venous bubble trap/venous air removing device; and a shed blood management system. Some of these items, alone or in combination, are able to modify the blood activation usually elicited by cardiopulmonary bypass (CPB). The hemostatic system activation is less activated and lower degrees of thrombin generation and platelet activation have been found in numerous studies. Additionally, the reduced level of hemodilution plays an important role in preserving clot firmness after CPB with MiECC. These biochemical changes are reflected by a blood loss containment, a reduced need for allogeneic blood transfusions, and, in some studies, by a lower thromboembolic complications rate. The activation of the inflammatory cascade is in turn limited by MiECC, both directly (through a blunting of the contact-phase activation) and indirectly (through a limited thrombin generation, platelet activation, and consequent lower release of pro-inflammatory cytokines). The clinical consequences of this are mainly demonstrated by a lower rate of postoperative atrial fibrillation; other inflammation-derived outcomes appear favorably affected by MiECC (lung function, acute kidney injury) but the multi-factorial nature of these complications makes difficult to clearly attribute this pattern to a lower degree of inflammation. Overall, the existing body of evidence is in favor of MiECC with respect to standard CPB.