BACKGROUND: The management of postoperative pain with traditional narcotic analgesic regimen is associated with an unacceptably high failure rate and at best has represented a cautious compromise between adequate analgesia and the risk of complications, particularly that of respiratory depression. The purpose of this investigation was to compare the efficacy and safety of nalbuphine given by patient-controlled analgesia (PCA) with differential dosages after total knee replacement. METHODS: A double-blind clinical trial of 75 patients who received intravenous nalbuphine with patient- controlled analgesia during the postoperative first 48 hours after total knee replacement, was carried. Patients were assigned to three groups by the concentration of nalbuphine: Group 1 (n = 25), 2 mg/ml; Group 2, 4 mg/ml; Group 3, 6 mg/ml. The settings of PCA in three groups were same. RESULTS: Visual analog scale (VAS) scores were used to assess pain. Group 2 and 3 patients reported significant lower VAS over the postoperatively 6 hours and 12 hours at either rest or movement compared to group 1. PCA demands, delivered doses and PCA nalbuphine dosage per hours except supplemental analgesic doses in the first 48 hours were lower in group 2 and 3 compared to group 1. There were significant differences among groups at postoperatively 6 and 12 hours in nausea, vomiting and sedation of the side effects. CONCLUSIONS: IV PCA with nalbuphine is thought to be potent and safe for postoperative pain relief without the major morbidity like respiratory depression, in addition, the careful observation and treatment on the side effect like nausea, vomiting and sedation, is surely needed.