The Yamamoto-Kohama (Y-K) mode of invasion is a useful indicator of the prognosis of squamous cell carcinoma (SCC) of the oral cavity. We have previously reported that the Y-K mode of invasion is related to lymph node metastasis in esophageal SCC. Therefore, to clarify the relationship between the Y-K mode of invasion and survival rate, we histologicaly evaluated specimens obtained by esophagectomy from patients who had not received induction therapy. The results indicated that the overall survival rate of patients with esophageal SCC was significantly lower in the Y-K 4D group. In addition, significantly lower expression of involucrin protein was observed in pStage III cases than in pStage II cases. As a consequence of the poor prognosis of pStage III SCC, it was suggested that involucrin expression was correlated with survival rate. In conclusion, the Y-K mode of invasion and involucrin expression are considered to be informative prognostic indicators in patients with esophageal SCC.