Recent studies have suggested an association between dietary folate, and related B-vitamins, and risk for cancer, potentially mediated by the p53 tumor suppressor gene. The aim of this study was to explore the effect of dietary folate and vitamin B 6 intake on p53 in the molecular pathogenesis of esophageal adenocarcinoma (EADC). For each participant, a structured questionnaire was used to obtain detailed sociodemographic and lifestyle risk factors, including diet, from which folate and vitamin B 6 intake were calculated. Risks for p53 mutations, p53 mutations at CpG sites, and p53 protein overexpression among EADC cases (n ¼ 54) were calculated using logistic regression with dietary folate and vitamin B 6 intake as predictive variables, adjusting for age, gender, smoking, and alcohol consumption. No significant differences were found for patients with EADC who had p53 mutations (n ¼ 21) compared with patients with wild-type p53 (n ¼ 33) with respect to selected clinicopathologic variables (age, gender, tumor grade, stage, alcohol, or tobacco consumption) and dietary intake of folate or vitamin B 6 . No statistically significant associations were seen between dietary folate and vitamin B 6 intake (highest vs. lowest quartiles) and p53 mutations, p53 mutations at CpG sites (n ¼ 12), and p53 protein overexpression (n ¼ 17). We conclude that dietary intake of folate and vitamin B 6 do not appear to have an effect on p53, suggesting alternative molecular mechanisms underlying esophageal adenocarcinogenesis.