Aims: To test the incidence of the expression of the immunohistochemical markers that aid diagnosis of gastrointestinal tract small cell carcinoma (GI-SmCC) and to evaluate the incidence of mixed endocrine-exocrine carcinomas in GI-SmCC. Methods: Immunohistochemical studies of three antibodies against epithelial markers (CK8, AE1/AE3, EMA), four neuroendocrine differentiation markers (synaptophysin (Syn), neuron specific enolase (NSE), neuronal cell adhesion molecules (CD56), chromogranin A (CgA)), and a transcription factor (thyroid transcription factor 1 (TTF-1)) were performed. The incidence of non-endocrine carcinoma component was evaluated in 42 GI-SmCCs (11 in the oesophagus, 15 in the stomach, 15 in the colon, and 1 in the small intestine). Results: The percentages of GI-SmCC with positive immunoreactivity were: CK8 92.9%, AE1/AE3 76.2%, EMA 71.4%, Syn 100%, NSE 100%, CD56 90.5%, CgA 61.9%, TTF-1 21.4%. The low molecular weight cytokeratin CK8 is more commonly expressed in GI-SmCC than is the expression of AE1/AE3 or EMA. Synaptophysin and NSE are expressed in all GI-SmCCs studied. Non-endocrine carcinoma components were demonstrated in 8 patients (4 in the oesophagus and 4 in the stomach). Conclusion: In detecting GI-SmCC, epithelial marker CK8 is more sensitive than AE1/AE3 or EMA, and neuroendocrine differentiation markers synaptophysin and NSE are the most useful markers. TTF-1 positivity is not uncommon in GI-SmCC, but cases with negative TTF-1 staining may indicate an extra-pulmonary primary. Non-endocrine carcinoma components were demonstrated in about 30% of oesophagus and stomach SmCC; the neoplasms should be diagnosed as mixed endocrine-exocrine carcinoma.