Controversy remains as to the need for neoadjuvant therapy in the treatment of cT2/T3N0M0 esophageal squamous cell carcinoma (ESCC), with regional (e.g., China vs. Japan) guidelines making divergent recommendations. Survival data suggest comparable overall survival (OS) rates among cII-stage patients. This study aimed to evaluate the efficacy of upfront surgery for cT2/T3N0M0-stage ESCC patients and to identify prognostic factors in this subgroup.We retrospectively collected the data of 786 cT2/T3N0M0-stage ESCC patients treated between January 2010 and December 2017 to assess the survival outcomes and identify risk factors. Additionally, we performed a survival analysis to explore the prognostic factors in this patient subgroup.The cT2N0-stage and cT3N0-stage ESCC patients had 5-year OS rates of 68.0% and 59.0%, respectively (median OS: 82.7 vs. 78.8 months, P=0.01). Postoperative adjuvant therapy significantly improved the OS of the cT3N0-stage patients compared to the cT3N0-stage patients those did not receive postoperative adjuvant therapy (5-year OS: 65% vs. 53%, P=0.004). Adjuvant therapy yielded comparable survival rates in the cT3N0-stage patients without perineural invasion (PNI) and the cT2N0-stage patients who underwent upfront surgery (5-year OS: 66% vs. 68%, P=0.42). Similarly, no significant difference was observed between the lymphovascular invasion (LVI)-negative cT3N0-stage patients those received adjuvant therapy after surgery and the cT2N0-stage patients those underwent upfront surgery (5-year OS: 66% vs. 68%, P=0.30). The survival analysis revealed no difference in OS between the highly differentiated cT3N0-stage and cT2N0-stage patients (5-year OS: 74% vs. 68%, P=0.79). Conversely, the lowly differentiated cT3N0-stage patients had a poorer prognosis with upfront surgery than the high and moderate differentiation patients and derived no survival benefit from adjuvant therapy (5-year OS: 55% vs. 68%, P=0.02). The multivariate analysis identified PNI as an independent prognostic factor for OS [hazard ratio (HR): 1.382; 95% confidence interval (CI): 1.037-1.841; P=0.03].Upfront surgery results in favorable long-term survival outcomes in cT2/T3N0M0-stage ESCC patients without PNI. These findings show the importance of tailoring therapeutic strategies to distinct ESCC subgroups, particularly based on PNI status and tumor differentiation.Copyright © 2025 AME Publishing Company. All rights reserved.