Purpose: This study was performed to compare the real-time electromyographic (EMG) changes and the rate of recurrent laryngeal nerve (RLN) injury in craniocaudal and lateral approaches for RLN during thyroidectomy. Methods: One hundred twelve and 86 patients were prospectively randomized to receive lateral (group 1) or craniocaudal (group 2) approach to RLN, respectively, under continuous intraoperative nerve monitoring. Results: Loss of signal (LOS) occurred in 7 (2.0%) of 356 nerves at risk (NAR). LOS was significantly associated with repeated adverse EMG changes and presence of RLN entrapment at the ligament of Berry (LOB), which was accompanied by other clinicopathological or anatomical features, such as tubercle of Zuckerkandl (TZ), extralaryngeal branching, hyperthyroidism, autoimmune thyroid disease (ATD), or thyroid lobe volume of >29 cm 3 (P = 0.001 and P = 0.030, respectively). The rate of repeated adverse EMG changes and LOS in the NARs with LOB entrapment accompanied by other clinicopathological and anatomical features was higher in group 1 vs. group 2 (11.1% vs. 2.2%, respectively and 9.7% vs. 0%, respectively; P = 0.070). The total rate of vocal cord palsy (VCP) was significantly higher in group 1 than in group 2 (P = 0.005). The rate of permanent VCP showed no significant difference between the 2 groups. Conclusion The craniocaudal approach to the RLN is safer than the lateral approach in the RLNs with entrapment at the LOB accompanied by other features, such as TZ, extralaryngeal branching, hyperthyroidism, ATD, or high thyroid lobe volume.