Background: The use of analgesics with different mechanism of action enhances post-operative pain relief by opioids. Both celecoxib and gabapentin have opioid-sparing effect, but it is unclear whether combination of the two drugs accentuates postoperative analgesia and further reduced opioid requirement. Objective: Determine whether the perioperative use of celecoxib in combination with gabapentin reduces the amount of post-operative opioid consumption in comparison to celecoxib alone or gabapentin alone in patients that have major orthopedic surgery. Materials and methods: Randomized double-blinded placebo controlled trial was done in 99 patients underwent major orthopedic surgery. They were randomly allocated into four groups. One to two hours before anesthesia, they received midazolam 7.5 mg plus study drugs. Group P received placebo plus placebo at 12 and 24 hours later. Group C received celecoxib 400 mg plus celecoxib 200 mg at 12 and 24 hour later. Group G received gabapentin 400 mg plus gabapentin 300 mg at 12 and 24 hour later. Finally, group CG received celecoxib 400 mg + gabapentin 400 mg plus celecoxib 200 mg + gabapentin 300 mg at 12 and 24 hour later. The patients underwent surgery under general anesthesia. Post-operative pain was treated by intravenous morphine patient-controlled analgesia. Results: Median morphine consumption (minimum-maximum) in twenty-four hours was 18.0, 15.0, 15.5, and 8.0 mg, in group P, C, G, and CG, respectively. The group CG significantly consumed less morphine (41%) in 24 hour than group G, but not significantly less (38%) than group C. Pain score, sedation score, and nausea/vomiting at postoperative hour 1, 4, 8, 12, 16, 20, and 24 was not significantly different. Conclusion: Combination of celecoxib and gabapentin further accentuated post-operative analgesia by morphine comparing to celecoxib or gabapentin alone without change in pain score and other side effects of the medications.Major orthopedic surgery, such as spine, major limb, and joint, usually causes moderate-to-severe postoperative pain that requires strong opioids to relief. The merit of strong opioids in severe pain reduction is obscured by its dose-related unwanted side effects. The concurrent use of more than one analgesic agent provided effective analgesia with smaller doses of each component, thereby minimizing adverse effects.Multimodality approaches for the treatment of postoperative pain have been widely practiced. Recently, several types of drug have been reported in many clinical trials, especially non-steroidal antiinflammatory drugs (NSAIDs) and coxibs. These drugs provide analgesic effect by inhibition of prostaglandins synthesis at the site of tissue injury and in the central nervous system. When given in perioperative period, they have shown significant opioid-sparing effect, reduction in opioid analgesic consumption, postoperative pain reduction, and patient satisfaction compared with placebo [1].