Thrombomodulin (TM) mediates blood coagulation and inflammation and is expressed constitutively on resting monocytes. This expression might be a key regulator of monocyte-related inflammation. Conventional cardiopulmonary bypass (CPB), beating-heart CPB, and off-pump techniques have been used widely in cardiac surgery. Although beating-heart CPB and off-pump techniques have reduced postoperative inflammation significantly, the underlying mechanisms remain unclear. Whether CPB affects the expression of TM and changes the actual immune capacity of monocytes is also unknown. In this study, we analyzed TM expression on monocytes and in plasma among patients undergoing elective coronary artery bypass graft surgery. The days spent in an intensive care unit (ICU) and incidence of fever in the ICU were significantly lower in the beating-heart CPB and off-pump groups than in the conventional CPB group. Enzyme-linked immunosorbent assay showed a significant increase in TM at 30 min after the commencement of CPB and at the end of surgery in the conventional CPB group, whereas the level increased less markedly in the beating-heart CPB group. Flow cytometry showed that conventional CPB markedly reduced the expression of TM on monocytes. Based on monocyte chemotaxis analysis and an actin polymerization assay, we propose that TM expression on monocytes is associated with systemic inflammation. We conclude that the beating-heart CPB and off-pump techniques have a lower impact on patients than conventional CPB. The reduced incidence of fever and shorter ICU stay seem to be associated predominantly with the lower concentration of TM in plasma and with a higher expression of TM on monocytes.