The objective of this work was to compare efficacy and adverse effects between vessel sealing system thyroid lobectomy (VSSL) with the new LigaSure™ Small Jaw Instrument and conventional thyroid lobectomy (CTL). This is a multicenter, randomized and controlled study, conducted in the Department of Otolaryngology, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok and Division of Otolaryngology, Sukhothai General Hospital, Sukhothai, Thailand. Forty subjects with solitary thyroid nodule planned for thyroid lobectomy were enrolled consecutively in both centers. Intervention was randomized by block randomization into two groups (VSSL, CTL). Primary outcomes were operative time and intraoperative blood loss. Secondary outcomes were postoperative blood loss and recurrent laryngeal nerve paralysis. There was clinically significant less operative time (VSSL/CTL = 62.4 ± 15.9/83.3 ± 16.1 min, p < 0.001) and less intraoperative blood loss (VSSL/CTL = 40.5 ± 19.1/63.3 ± 22.4 mL, p = 0.001) in VSSL group compared with CTL group. There was no significant difference of postoperative blood loss (VSSL/CTL = 58.8 ± 30.6/76.0 ± 36.9 mL, p = 0.116) between both the groups. There was one case of permanent recurrent laryngeal nerve injury found in both groups. VSSL with the new LigaSure™ Small Jaw Instrument was better than conventional technique in terms of shortening operative time. It was also better in reducing intraoperative hemorrhage, but this effect did not exceed clinically significant levels. Postoperative blood loss and recurrent laryngeal nerve injury were not significantly different between both the groups.