PurposeRadical lymph-node dissection surgery in patients with cN0 middle thoracic esophageal squamous cell carcinoma (ESCC) remains controversial. We sought a novel biomarker that could be used for decision-making in relation to radical lymph-node dissection.MethodsOne hundred and nineteen patients with cN0 middle thoracic ESCC undergoing three-field lymph-node dissection (3FLND) or two-field lymph-node dissection (Ivor Lewis) esophagectomy were reviewed. A survival analysis, and Chi-square and parametric tests were performed.ResultsA Cox regression analysis revealed that the expression of BRF2 was an independent prognostic factor for overall survival (P = 0.014) and progression-free survival (P = 0.014). The survival of patients who underwent 3FLND was better than that of patients who underwent Ivor Lewis esophagectomy in the BRF2 overexpression group (P = 0.002), but not in the BRF2 nonoverexpression group (P = 0.386). The risk of lymph-node recurrence and the number of recurrent lymph nodes in patients with the overexpression of BRF2 were increased in the Ivor Lewis group in comparison to the 3FLND group (P = 0.01 and P < 0.001). The risk of cervical and superior mediastinal lymph-node recurrence was positively correlated with the overexpression of BRF2 (P = 0.027). Furthermore, in the Ivor Lewis group, a significant correlation was found between the risk of lymph-node recurrence or the number of recurrent lymph nodes and the expression of BRF2 (P = 0.002 and P = 0.004), but not in the 3FLND group (P = 0.193 and P = 0.694).Conclusions3FLND generated better survival outcomes and reduced the rate of lymph-node recurrence in comparison to Ivor Lewis in patients with the overexpression of BRF2. BRF2 can be used as an indicator for radical lymph-node dissection surgery in cN0 ESCC patients.