The objective of the study is to compare the outcome of total thyroidectomy (TT) using the Harmonic Focus™ (HF) versus conventional "knot tying" (KT) in terms of operative time, parathyroid function and post-operative complications. This prospective study was designed with a random allocation of subjects using a drawing technique. Eighty-one consecutive patients were submitted to TT in 2010 and randomly divided into two groups: 43 patients operated using HF (HF group) and 38 patients operated using KT (KT group). Parathyroid function was evaluated by parathyroid hormone (PTH) level at 1 h postoperatively and calcium level at first post-operative day. Indications for medical therapy were PTH < 15 pg/ml and/or calcium < 8.0 mg/dl and/or clinical signs or symptoms of hypocalcemia. Main outcomes were operative time, PTH and calcium levels, need for medical therapy and post-operative complications. Mean operative time was significantly lower in HF group compared with KT group (100 ± 34 vs. 119 ± 30 min). There were no significant differences concerning transient hypoparathyroidism requiring calcium and/or vitamin D therapy: 17 patients (39.5%) in HF group versus 21 (55.3%) in KT group. Five patients (11.6%) in HF group experienced symptomatic hypocalcemia versus 6 (15.8%) in KT group, without statistically significant difference. No patients experienced recurrent nerve injury. HF is a new ergonomic, reliable device developed for thyroid surgery. According to our results, HF is a safe, time-saving alternative to "knot tying" thyroidectomy, with no influence on parathyroid function, medical therapy and nerve injury.