BACKGROUND: As optimal pain relief after surgery is difficult to achieve with the use of just one drug, many pain experts advocate the use of two or more classes of medications so as to reduce the side effects from any one drug. In this trial, we assessed the analgesic efficacy of administering perioperative celecoxib, pregabalin, or both after spinal fusion surgery. METHODS: Eighty patients scheduled to undergo elective decompressive lumbar laminectomy with posterior spinal fusion were randomized to receive oral medications: placebo 1 h before and 12 h after surgery, celecoxib 400 mg 1 h before and celecoxib 200 mg 12 h after surgery, pregabalin 150 mg 1 h before and 12 h after surgery, or a pregabalin/celecoxib combination of 400 mg/150 mg 1 h before and 200 mg/150 mg 12 h after surgery. RESULTS: The pregabalin/celecoxib group consumed the least patient-controlled morphine. Celecoxib alone or pregabalin alone also reduced opioid use compared with placebo, but not as much as when combined. The pregabalin/celecoxib combination was the most effective treatment for reducing pain both at rest and with movement over the 24-h postoperative time period. Hemodynamics and respiratory rate did not differ among the four treatment groups. Fewer patients experienced nausea in the pregabalin/celecoxib group compared with that in the placebo group. CONCLUSION: The perioperative administration of the combination of celecoxib and pregabalin improved analgesia and caused fewer side effects, than either analgesic drug alone after spinal fusion surgery.