Objective To compare the clinical efficacy between air-free trans-axillary laparoscopic thyroidectomy and open thyroidectomy. Methods A retrospective analysis was performed on the data of both 96 patients who underwent air-free trans-axillary laparoscopic thyroidectomy (laparoscopic group) and 232 patients who underwent open thyroidectomy (open group) from August 2015 to July 2020. Comparative analysis were performed on operative data, the postoperative data of recovery and complications between two groups. Results The operative time in laparoscopic group was longer significantly than that in open group [(168±23) min vs. (95±18) min, P=0.022]. There was no significantly difference in the rate of recognition of recurrent laryngeal nerve between two groups (100.0% vs. 99.1%, P=0.138). The rate of recognition of both superior (98.0% vs. 97.0%, P=0.003) and inferior parathyroid glands (95.8% vs. 99.1%, P=0.028) in laparoscopic group was higher significantly than those in open group. The amount of drain of the first day after operation in laparoscopic group was more significantly than that in open group[(42±22) mL vs. (25±10) mL, P=0.006]. The postoperative length of hospital stay in laparoscopic group was longer significantly [(2.8±0.6) d vs. (1.8±1.2) d, P=0.016]. The cost of hospital stay was (13 186±1 015) yuan vs. (12 632±1 456) yuan （P=0.365） and the rate of postoperative complication was 10.4% vs. 9.1%（P=0.126）, which all showed no significant difference between two groups. Conclusions Air-free trans-axillary laparoscopic thyroidectomy could be feasible and safe, and have better appearance. However, both operative time and hospital stay were longer.