We monitored serum p53 antibody (s-p53-Ab) titers in a 76-year-old man with esophageal adenocarcinoma, clinical stage III (T2N2M0), for over 4 years, including during the perioperative period and throughout follow-up after surgery. Screening tests for CA19-9 (205 IU/ml) and s-p53-Abs (381 U/ml) were positive before treatment. After neoadjuvant chemotherapy with 5-FU and cisplatin, CA19-9 decreased to the normal range, but the s-p53-Ab titer remained positive (224 U/ml). Pathological findings of surgically resected specimens showed stage T1b disease and no lymph node metastases. After surgery, s-p53-Ab titers consistently decreased, with no disease recurrence. Although the s-p53-Ab titer remained positive even after 4 years, it decreased to 8.66, 3.59, 2.38, and 1.92 U/ml, 1, 2, 3, and 4 years after surgery, respectively. Thus, monitoring perioperative changes in s-p53-Ab titers proved useful for detecting the presence of residual cancer cells in a patient with superficial esophageal adenocarcinoma.