The systemic inflammatory response after coronary artery bypass grafting using cardiopulmonary bypass (CPB) contributes substantially to postoperative organ dysfunction and coagulation disorders. Important features of this inflammatory reaction include the activation of complement and leukocytes, the release of proinflammatory cytokines, alterations in the metabolism of nitric oxide, and an increase in the production of oxygen-free radicals, which in some cases may lead to oxidant stress injury. Several strategies including the use of steroids, use of aprotinin, heparin-coated CPB circuits, and hemofiltration have been reported to reduce the inflammatory reaction induced by CPB and its consequences. A more radical and effective way of counteracting the effects of the inflammatory reaction and oxidative stress may be the omission of CPB itself. The development and application of off-pump coronary artery bypass (OPCAB) technology has largely been driven by this theme of avoiding systemic inflammatory reaction to decrease the incidence and/or severity of adverse outcomes. This review article discusses the influence of cardiopulmonary bypass on systemic inflammation and attempts to evaluate the current best available evidence on the impact of OPCAB on systemic inflammation.