This clinical trial evaluated the effect of preemptive use of the non-steroidal anti-inflammatory drug piroxicam in a single dose 30 min prior to in-office bleaching on the prevention of tooth sensitivity (TS) reported by patients. Fifty patients were submitted to two sessions of in-office tooth bleaching with 35% hydrogen peroxide used for 2 sessions, each consisting of a single 45-min application, with an interval of 7 days between session. Thirty minutes prior to the procedure, the patient randomly received a single dose of piroxicam (200 mg) or placebo in a double-blind, randomized, crossover design. The TS was evaluated using verbal rate (VRS) and visual analog (VAS) scales during the bleaching procedure and at 24 h after each session. The color changes were assessed by the Vita Bleachedguide scale 1 week after each bleaching session. Risk of TS was calculated from the VRS and analyzed by the McNemar test, while the level of TS was analyzed by the Mann-Whitney test. For the VAS, t-tests were used to compare data from the treatments at each assessment time. Data regarding color changes were subjected to Wilcoxon and Mann-Whitney tests (α=0.05). The preemptive administration of piroxicam did not affect the risk and level of TS compared to placebo, irrespective of the assessment time. The treatment sequence did not affect bleaching effectiveness. In conclusion, the administration of a single dose of piroxicam prior to in-office tooth bleaching was unable to significantly reduce the risk and level of TS.