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Epidural anesthesia has been suggested to exert a protective effect against the inflammatory and stress responses associated with surgery. The aim of this study was to evaluate the impact of thoracic epidural anesthesia on myocardial cell damage, inflammatory, and stress responses in patients undergoing off-pump coronary artery bypass graft (OPCABG) surgery.Seventy-four patients (66 male [89%], mean age 65.2 years [SD 9.6]) undergoing OPCABG surgery were randomly assigned to receive either general anesthesia plus epidural (GAE [n = 36]) or general anesthesia only (GA [n = 38]). Troponin I, 8-isoprostane, cortisol, C3α, interleukin (IL)-6, IL-8, and IL-10 were measured preoperatively, at 30 minutes, and 4, 12, 24, and 48 hours postoperatively.Baseline characteristics were similar in the two groups. One patient died in the GAE group, but no other major postoperative complications were recorded in either group. The IL-6 and IL-8 levels were lower in the GAE group (ratio 0.83, 95% confidence interval: 0.68 to 1.02;p= 0.070) than in the GA group (ratio 0.90, 95% confidence interval: 0.78 to 1.02;p= 0.090). The difference in levels of IL-10 between the GAE and GA groups varied over time (p≳ 0.001). The C3α, troponin I, 8-isoprostane, and cortisol release was similar in the two groups throughout (p≥ 0.12).Thoracic epidural anesthesia does not provide any additional benefits in terms of reducing myocardial damage, inflammatory, and stress response compared with general anesthesia only in patients undergoing OPCABG surgery.