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Background: New ways of decreasing post-operative analgesic drug requirements are of special interest after major surgery. Magnesium sulfate (MgSO4) alters pain processing and reduces the induction and maintenance of central sensitization by blocking the N-methyl-d-aspartate (NMDA) receptor in the spinal cord. We investigated whether supplementation of spinal anesthesia with combined intrathecally and epidurally infused MgSO4 reduced patients’ post-operative analgesia requirements. Methods: In a randomized, prospective, double-blind, placebo-controlled trial, we enrolled 120 consecutive patients undergoing orthopedic surgery during spinal anesthesia (levobupivacaine and sufentanil). Patients were randomly assigned to receive intrathecal MgSO4 (94.5 mg, 6.3%), epidural MgSO4 (2%, 100 mg/h), intrathecal and epidural MgSO4 combined or spinal anesthesia alone (controls). Post-operative morphine consumption was assessed in all groups by patient-controlled analgesia (PCA). Results: Of the 120 patients enrolled, 103 (86%) completed the study. Morphine consumption at 36 h after surgery was 38% lower in patients receiving spinal anesthesia plus epidural MgSO4 [– 14.963 mg; 95% confidence interval (CI), – 1.44 to – 28.49 mg], 49% lower in those receiving spinal anesthesia plus intrathecal MgSO4 (– 18.963 mg; 95% CI, – 5.27 to – 32.65 mg) and 69% lower in the intrathecal–epidural combined group (– 26.963 mg; 95% CI, – 13.73 to – 40.19 mg) relative to control patients receiving spinal anesthesia alone. No complications developed during the post-operative course or at 1 month after surgery. Conclusion: In patients undergoing orthopedic surgery, supplementation of spinal anesthesia with combined intrathecal and epidural MgSO4 significantly reduces patients’ post-operative analgesic requirements. [ABSTRACT FROM AUTHOR]