Pre-operative chemotherapy is increasingly used in the treatment of oesophageal carcinoma. However, no features have been identified which can reliably predict a positive response to chemotherapy. The aim of this study was to examine whether histological features and p53 overexpression could predict such response. Prechemotherapy endoscopic biopsies from 55 patients, who subsequently completed two courses of chemotherapy followed by surgical resection, were studied. Patients were classified into responders and non-responders according to clinical and pathological findings. Pathological features of the endoscopic biopsies examined included adequacy of the tumour tissue, histological grade, degree of keratinisation, histologic patterns, mitotic rates and nuclear pleomorphism. Biopsy specimens were also tested for p53 overexpression using p53 protein specific mouse monoclonal antibody DO-7 on paraffin sections. Histologic features and p53 expression were correlated to chemoresponsiveness. 76% (42 of 55) of patients had sufficient biopsy tissue for assessment. Response to chemotherapy was evident in 64% (n = 27) of patients. None of the non-responders had tumours with high-grade nuclear pleomorphism compared with 37% (10 of 27) of responders (P = 0.01). All patients with high-grade nuclear pleomorphism responded to chemotherapy. No significant differences were found between the responders and non-responders with respect to tumour differentiation (P = 0.7), degree of keratinisation (P = 0.3) and mitotic rates (P = 0.8). Overall, p53 overexpression was noted in 67% (28 of 42) of patients. This was more prevalent in non-responders (12/15) compared to responders (16/27), but this was not statistically significant (P = 0.08). The degree of p53 overexpression had no significant relationship with responsiveness to chemotherapy. High-grade nuclear pleomorphism, identified on pretreatment biopsy specimens, correlated with response to chemotherapy, whereas p53 overexpression did not correlate with response. Improved tissue sampling and further investigations should be done so that the assessment of prechemotherapeutic endoscopic biopsies can have significant impact on clinical decision making.