The aim of this study was to compare the efficacy of topical piroxicam and EMLA cream on pain control and subsequent inflammation in neodymium:yttrium-aluminum-garnet (Nd:YAG) 1,064 nm laser hair removal in female volunteers. Fifty female volunteers were enrolled in this prospective, randomized, double-blind, clinical study over a 6-month period. Patients were randomly assigned to receive topical piroxicam as group Piroxicam or EMLA cream as group EMLA. Topical analgesics were applied to the treatment sites for 60 min. The pain scores [on a visual analog scale (VAS)] and side effects were recorded before the hair removal, during the hair removal, at the end of the hair removal, and 1 h, 2 h and 24 h after the hair removal. Patients' characteristics and the treatment settings of the Nd:YAG 1,064 nm laser were similar in the two groups. The pain scores (VAS) were similar, and satisfaction was high in both groups after the hair removal. The number of blanching and erythema episodes were significantly higher in group E than in group P (P < 0.001). Inflammatory side effects were less frequent in group P than in group E after the procedure (P < 0.001). This study showed that topical piroxicam and EMLA provided adequate and similar pain relief after Nd:YAG 1,064 nm laser hair removal in female volunteers. Topical piroxicam was associated with fewer inflammatory side effects than was EMLA cream, because of its anti-inflammatory effect after the procedure.