Introduction: Orthodontic therapy causes significant pain for a large percentage of patients. It is one of the main reasons that discourage patients from seeking orthodontic treatment. Pain during orthodontic treatment may have a negative influence on cooperation and can also reduce the compliance. This study assessed the effectiveness of a single dose of preoperative Piroxicam in reducing the incidence and severity of pain after orthodontic separator placement when compared to ibuprofen. Materials and Methods: The study was a randomized, placebo-controlled, double-blind, parallel-arm study. Sixty eight patients were recruited for this study and were randomly assigned to one of the three experimental groups: 1. 20 mg of Piroxicam followed by two doses of multivitamin placebo ( n = 30); 2. 400 mg of Ibuprofen in three doses ( n = 20) and 3. A multivitamin placebo ( n = 18). All the three groups were administered the first dose of the respective medication one hour prior to separator placement, the successive two doses were given at 3 hours and 7 hours after separator placement. The pain experienced by the patient was assessed at the time intervals 2 hours, 4 hours, 6 hours, bedtime, on awakening the following day and 24 hours after administration using a visual analogue scale. Results: A comparison of pain perception between all three groups with the repeated measures analysis of variance (ANOVA) and a comparison of pain perception between the first and second group using the Student t test revealed that preemptive Piroxicam therapy significantly lower pain levels experienced at all-time intervals starting from 2 hours after separator placement till 24 hours after placement. Conclusion: A single dose of Piroxicam taken 60 minutes before separator placement reduces pain due to separator placement experienced in the first 24 hours following separator placement.