BACKGROUND Cardiac surgery with cardiopulmonary bypass has a major impact on the congenital immune response, in which Toll-like receptors (TLRs) are the first line of defence. Decreased surface expression of TLRs and impaired monocyte responsiveness to TLR ligands occur following surgery. However, the clinical implications of this altered immune response are not clear. OBJECTIVES To study cardiac surgery induced changes in perioperative TLR expression and monocyte responsiveness, and the association with postoperative inflammatory complications. DESIGN A prospective cohort study. SETTING Single university hospital, enrolment March to December 2007. PATIENTS Eighty-four out of 92 patients who underwent coronary artery bypass grafting (CABG) were followed up until hospital discharge. MAIN OUTCOME MEASURES We assessed in-vivo TLR-2 and TLR-4 expression and ex-vivo monocyte responsiveness to TLR-2 and TLR-4 ligands, measured by Pam3Cys and lipopolysaccharide (LPS)-induced interleukin (IL)-6 and IL-8, and tumour necrosis factor alpha (TNF-alpha) secretion until 24 h after surgery. Patients were followed to identify adverse inflammatory and infectious outcomes. RESULTS Monocyte TLR expression decreased during CABG but returned to baseline after 24 h [linear mixed effects (LME) over time P <0.0001]. Monocyte responsiveness changed significantly over time, with marked postoperative hyporesponsiveness (LME P <0.0001). Decreased monocyte responsiveness to LPS was associated with monocyte TLR-4 expression (LME for IL-6 P = 0.04, IL-8 P = 0.002, TNF-alpha P = 0.05). Intraoperative decrease of monocyte TLR-2 expression was associated with postoperative systemic inflammatory response syndrome (SIRS) and pneumonia [ odds ratio (OR) 2.06, 95% confidence interval (95% CI) 1.14 to 3.72], but the perioperative decrease of monocyte TLR-4 expression was not (OR 1.10, 95% CI 0.80 to 1.52). CONCLUSION CABG surgery induced a decrease in in-vivo monocyte TLR expression and also in ex-vivo monocyte responsiveness, with which monocyte TLR-4 expression and monocyte LPS responsiveness seemed to be associated. Decreased TLR-2 expression was associated with the occurrence of SIRS and pneumonia, suggesting a role in the cause of postoperative inflammatory conditions.