Cardiopulmonary bypass (CPB) has been recognized as a cause of complex systemic inflammatory response, which significantly contributes to several adverse postoperative complications. In the last few years, off-pump coronary artery bypass grafting has gained widespread diffusion as an alternative technique to conventional on-pump coronary artery bypass grafting. Surgeons supporting off-pump surgery state that the avoidance of the CPB and myocardial ischemia-reperfusion significantly reduces the postoperative systemic inflammatory response and other biological derangements and, possibly, may improve the clinical outcomes. We review, here, the available evidence concerning possible differences between off-pump and on-pump procedures in terms of inflammation, hemostasis and oxidative stress. Consistent differences in the involvement of these systems are observed, but they are limited to the final steps of the surgical procedures and the early hours after. These findings suggest that the global surgical trauma may be as important, or even more, as the CPB in terms of systemic inflammatory and coagulation-fibrinolytic pathway activation. Further studies are needed in order to confirm this hypothesis.