Background: Severe preamputation pain is associated with phantom limb pain (PLP) development in limb amputees. We investigated whether optimized perioperative analgesia reduces PLP at 6-month follow-up. Methods: A total of 65 patients underwent lower-limb amputation and were assigned to five analgesic regimens: (1) Epi/Epi/Epi patients received perioperative epidural analgesia and epidural anesthesia; (2) PCA/Epi/Epi patients received preoperative intravenous patient-controlled analgesia (PCA), postoperative epidural analgesia, and epidural anesthesia; (3) PCA/Epi/PCA patients received perioperative intravenous PCA and epidural anesthesia; (4) PCA/GA/PCA patients received perioperative intravenous PCA and general anesthesia (GA); (5) controls received conventional analgesia and GA. Epidural analgesia or intravenous PCA started 48 h preoperatively and continued 48 h postoperatively. The results of the visual analog scale and the McGill Pain Questionnaire were recorded perioperatively and at 1 and 6 months. Results: At 6 months, median (minimum-maximum) PLP and P values (intervention groups vs. control group) for the visual analog scale were as follows: 0 (0-20) for Epi/Epi/Epi (P = 0.001), 0 (0-42) for PCA/Epi/Epi (P = 0.014), 20 (0-40) for PCA/Epi/PCA (P = 0.532), 0 (0-30) for PCA/GA/PCA (P = 0.008), and 20 (0-58) for controls. The values for the McGill Pain Questionnaire were as follows: 0 (0-7) for Epi/Epi/Epi (P < 0.001), 0 (0-9) for PCA/Epi/Epi (P = 0.003), 6 (0-11) for PCA/Epi/PCA (P = 0.208), 0 (0-9) for PCA/GA/PCA (P = 0.003), and 7 (0-15) for controls. At 6 months, PLP was present in 1 of 13 Epi/Epi/Epi, 4 of 13 PCA/Epi/Epi, and 3 of 13 PCA/GA/PCA patients versus 9 of 12 control patients (P = 0.001, P = 0.027, and P = 0.009, respectively). Residual limb pain at 6 months was insignificant. Conclusions: Optimized epidural analgesia or intravenous PCA, starting 48 h preoperatively and continuing for 48 h postoperatively, decreases PLP at 6 months.