Purpose The surgical removal of mandibular third molars is frequently accompanied by significant postsurgical sequelae, and different protocols have been described to decrease such adverse events. The aim of this study was to investigate the performance of piezosurgery compared with traditional rotating instruments during mandibular third molar removal. Patients and Methods A single-center, randomized, split-mouth study was performed using a consecutive series of unrelated healthy patients attending the Oral Surgery Unit of the University of Turin for surgical removal of bilateral mandibular third molar teeth. Each patient was treated, at the same appointment, using bur removal on 1 side of the mandible and a piezoelectric device on the contralateral side. The primary outcomes reported were postoperative pain, objective orofacial swelling, and surgical duration; secondary outcomes were gender, age, and possible adverse events. Analysis of variance or paired t test was used as appropriate to test any significant differences at baseline according to each treatment subgroup, and categorical variables were analyzed by χ2 test. Results The study sample consisted of 100 otherwise healthy patients. The mean pain evaluation reported by patients who underwent surgery with piezosurgery was significantly lower than that reported after bur (conventional) removal, reaching statistical difference after 4 days (P = .043). The clinical value of orofacial swelling at day 7, normalized to baseline, was lower in the piezosurgery group (P < .005). The average surgical duration was significantly shorter in the bur group than in the piezosurgery group (P < .05). Three patients having bur removal developed short-term complications (2 dry sockets and 1 temporary paraesthesia), which totally resolved by 4 weeks. Conclusions To date, this prospective investigation is the largest reported split-mouth study on piezosurgery for lower third molar tooth removal. This study also compared surgeons with different degrees of experience. It is evident that using a piezoelectric device can enhance the patient experience and decrease postoperative pain and swelling.