A 66-year-old man presented with dysphagia and a cervical mass. Initial imaging showed an enlarged left cervical lymph node but no intra-abdominal metastasis. Esophagogastroduodenoscopy and histopathologic evaluation of the primary lesion and cervical lymph node led to the diagnosis of esophageal squamous cell carcinoma (ESCC) with cervical lymph node metastasis. Notably, the serum anti-p53 antibody level was elevated to 191.2 U/mL (normal range: ≤1.3 U/mL
measurement method: chemiluminescent enzyme immunoassay). The patient began chemoradiotherapy (CRT) with cisplatin and 5-fluorouracil, leading to the substantial shrinkage of the primary esophageal tumor. However, within weeks, he developed peritoneal dissemination and carcinomatous peritonitis, ultimately passing away. The autopsy revealed widespread peritoneal dissemination, mesenteric obstruction, and systemic lymph node metastases. Peritoneal dissemination and metastasis to the skin and intestine of ESCC are relatively rare. This case illustrates the potential prognostic significance of high serum anti-p53 antibody levels in ESCC, suggesting a link to aggressive disease progression and early metastatic spread. Elevated anti-p53 levels, correlating with strong p53 tumor immunoreactivity, may indicate a poor prognosis in ESCC, though further investigation is needed. This case highlights the need for close monitoring of ESCC patients with elevated serum anti-p53 antibodies, which could serve as markers for metastatic risk and therapeutic responsiveness, warranting further study in ESCC management strategies.