The incidence of gastro-oesophageal junction (GEJ) adenocarcinoma is increasing in Western countries and prognosis is poor since metastasis is most often present at diagnosis. We examined samples from 87 resected type II GEJ adenocarcinomas, 30 of these with endoscopic diagnostic biopsy material, to evaluate transforming growth factor alpha (TGF-a) expression and p53 overexpression by immunohistochemistry and in situ hybridization (for TGF-alpha), in relation to biological and clinical behaviour. TGF-alpha messenger RNA (mRNA) and protein were detectable in neoplastic cells in 56% and 64% cases respectively. TGF-alpha mRNA was detected in intra- and peritumoral lymphocytes and those of metastatic lymph nodes. TGF-alpha protein expression was significantly associated with tumour progression (P= 0.025) and lymph node metastasis (P < 0.05). The strong TGF-alpha expression found in neoplastic cells inside blood and lymphatic vessels and in metastatic localizations suggests that TGF-a-positive GEJ adenocarcinomas could have a more aggressive biological phenotype. The expression of TGF-alpha mRNA and protein in both inflammatory and neoplastic cells indicates that TGF-alpha is directly synthesized by both cell compartments. Finally, since TGF-alpha expression was associated with lymph node metastasis, its detection in preoperative perendoscopic biopsies might identify patients with more aggressive tumours who may need additional therapy, including neo-adjuvant treatment.