To evaluate the possibility of treatment with antiepidermal growth factor receptor (EGFR) mAb, Cetuximab against esophageal squamous cell carcinoma (SCC), we performed detail analysis of the antibody-dependent cellular cytotoxicity (ADCC) mediated by Cetuximab against esophageal SCC. Esophageal SCC cell lines with various levels of EGFR (n = 8) were evaluated for their Cetuximab-mediated ADCC by (51)Cr-release assay. As a result, Cetuximab was able to induce ADCC against EGFR-expressing esophageal SCC and the activities reflected the degree of EGFR expression on the esophageal SCC. The activities of Cetuximab-mediated ADCC by patients' PBMC were impaired in comparison with those by healthy donors' PBMC. Moreover, the inhibition of transforming growth factor (TGF)-beta could enhance Cetuximab-mediated ADCC against TGF-beta-producing SCC. In conclusion, Cetuximab was able to induce ADCC against EGFR-expressing esophageal SCC. Some modalities aiming at enhancing the Cetuximab-mediated ADCC may be necessary for successful Cetuximab treatment of patients with esophageal SCC.