This study evaluates the clinical significance of p53 mutations in oesophageal adenocarcinoma (EADC).Between February 1991 and February 2006, 142 consecutive patients with EADC underwent potentially curative oesophageal resection. No patient received induction therapy. Strict clinicopathologic criteria were used to define primary EADC (Type I), excluding gastric cardia adenocarcinoma (Type II). Genomic DNA was extracted from oesophageal tumours, each with matched histologically normal oesophageal epithelium (internal control) from the resection margin. Polymerase chain reaction was used to amplify p53 exons 4-10, and mutations were characterised by direct DNA sequencing. The p53 mutations were correlated with clinicopathologic findings, p53 protein expression determined using immunohistochemistry, and outcome using Kaplan-Meier and Cox proportional hazards models.For all patients, 5-year overall survival (OS) was 26.9%. Conventional predictors of reduced OS included advanced pathological tumour-node-metastasis (pTNM) stage (P3; P<0.0001). No p53 mutations were found in normal oesophageal epithelia. A total of 47% of tumours (67/142) had p53 mutations, predominantly G:C to A:T transitions at CpG dinucleotides (36/67). The p53 mutations were associated with p53 protein overexpression (P<0.0001) and poor tumour differentiation (P=0.037). Patients whose tumours had p53 mutations had significantly reduced 5-year OS (hazard ratio (HR): 1.54; 95% confidence interval (CI): 1.03-2.3; P=0.03).Patterns of p53 mutations in EADC suggest endogenous molecular mechanisms. The p53 mutations are a predictor of significantly reduced postoperative survival following surgical resection of EADC, and would appear to be a clinically useful molecular prognostic biomarker.