Background <p>This study aimed to determine whether serum squamous cell carcinoma antigen (SCC) value before and after neoadjuvant chemotherapy (NAC) can help to predict pT4 locally advanced esophageal squamous cell cancer (ESCC).</p> Methods <p>The study included 117 ycT3 ESCC patients who received NAC and underwent esophagectomy. The patients were categorized into ycT3r and ycT3br groups according to the 12th edition of the Japanese Classification of Esophageal Cancer. All SCC values before NAC (pre-SCC) and after NAC (post-SCC) as well as the difference between post-SCC and pre-SCC values (ΔSCC) were examined to determine their association with pT4.</p> Results <p>Pre-SCC levels did not differ significantly across pT stage (<i>P</i> = 0.267), whereas post-SCC levels showed a significant pT stage-dependent variation (<i>P</i> = 0.005). Only pT4 patients exhibited a positive ΔSCC value and showed significant pT-dependent variation (<i>P</i> = 0.002). The highest area under the receiver operating characteristic (ROC) curve for predicting pT4 was achieved by ΔSCC, at 0.779 (<i>P</i> &lt; 0.001), followed by post- and pre-SCC, using the cutoff value of 0.4 determined by the Youden index. Multivariate analysis identified ycT3br (<i>P</i> = 0.004) and ΔSCC ≥0.4 (<i>P</i> = 0.003) as independent predictors for pT4. Among the patients with ycT3r and ΔSCC &lt;0.4, 98.8% had a diagnosis of pT3, yielding a higher negative predictive value for adjacent organ invasion than ycT staging would have alone (92.4%). Among those with ycT3br and ΔSCC ≥0.4, 50% had a diagnosis of pT4, showing a higher positive predictive value for adjacent organ invasion than ycT staging would have alone (32.4%).</p> Conclusions <p>Integrating ΔSCC into CT-based assessment may improve predictive ability for pT4.</p>