Esophageal cancer is the 6th most common cancer in the world, and genetic factors (p53 mutations) in addition to the environmental factors (food, nutrition, smoking, drinking, etc.) are involved in its development. In this study, the association between the both factors, environmental risk factors for esophageal cancer and p53 mutations, in tumor tissues was investigated in 77 patients living in a high-incidence area and 50 patients living in a low-incidence area in Hebei Province, China. Among these patients, p53 mutations were observed in about 50%, without regional differences in the respective frequencies. G:C>A:T (G to A or C to T) transition mutations were the major type of mutations observed in patients in the high-incidence area (19 patients, 50%), whereas G:C>A:T transitions and insertions were observed with equal frequency (8 patients, 33.3%) in the low-incidence area. As for the association with environmental factors, p53 mutations occurred with higher frequency in patients with a daily intake of spicy foods and in those who used unboiled well water in the low-incidence area. Logistic regression analysis showed no association between food intakes and p53 mutations in high- and low-incidence areas. Thus, higher frequency of spicy food intake and use of unboiled well water may be risk factors of esophageal cancer via p53 mutations in China.