Objective: To investigate the efficacy and safety of the use of harmonic scalpel in open thyroid surgery. Methods: Using a prospective randomized controlled trial design, 210 patients from February 2010 to May 2012 were divided into harmonic scalpel group and electric scalpel group with 105 cases in each group, and underwent open thyroidectomy with harmonic scalpel and conventional electric scalpel, respectively. All operations were completed by the same surgical team with a wide experience in thyroid surgery. The operative time, intraoperative blood loss and postoperative drainage volume for the same type of surgery, and postoperative complications between the two groups were compared. Results: There was no significant difference in age, sex, tumor size or type of disease between the two groups (all P>0.05). The operative time, intraoperative blood loss and postoperative drainage volume for the same type of surgery in harmonic scalpel group were all reduced compared with electronic scalpel group, with all differences reached a statistical significance (all P<0.05). No statistical difference was noted in postoperative complications between the two groups (P>0.05). Conclusion: Harmonic scalpel combines hemostasis and sectioning in a single instrument, which simplifies the surgical procedure; use of harmonic scalpel in open thyroid surgery can shorten operative time and reduce intraoperative bleeding.