The p53 and p21 genes are closely related to sensitivity to chemoradiotherapy.The expressions of the p53 and p21 genes were immunohistochemically examined in 32 patients with esophageal cancer, who underwent an esophagectomy after hyperthermochemoradiotherapy (HCRT). The significance of the expression of these genes for the effect of HCRT was evaluated.HCRT was markedly effective (grade 3 response: no residual viable cancer cells) in 12 cases (38%). The incidences of the grade 3 were 67% and 20% in the cases with a positive and negative p21 expression, respectively (p=0.0213). A multivariate analysis revealed the p21 expression to be a significant independent factor associated with the histological effects. None of the 10 patients with p53-positive and p21-negative tumors showed a grade 3 response, while 55% showed grade 3 response in other combination groups (p < 0.05).The combination of p53 and p21 expressions in biopsy findings can thus predict the histological effectiveness of HCRT.