Although esophageal squamous cell carcinoma (ESCC) patients have recently been treated with the combined modality therapy, the prognosis remains poor. For the development of new strategies in ESCC, we examined possibilities of the immune -based therapy with cytotoxic T lymphocyte (CTL) and the molecular targeting therapy for HER2 against ESCC in this study. At first, we assessed HER2 and MHC class I expression by immunohistochemistry in ESCC patients and analyzed the correlation between them. Subsequently, the effect of molecular targeting therapy for HER2 was evaluated in a panel of ESCC cell lines. According to these results, we suggested that HER2 over-expressing ESCC patients (11.8%) are good candidates for the molecular targeting therapy for HER2 and HER2 negative/low-expressing ESCC patients (88.2%) for the immune-based therapy with CTL. Furthermore, the combination therapy of Herceptin and lapatinib is a new promising strategy for HER2 positive ESCC patients (29.4%).