Regulated secretory vesicles of neuroendocrine cells encompass two distinct types, i.e. hormone-storing large dense core vesicles (LDCV) and neuron-like small synaptic vesicles (SSVs). The membranes of the vesicles and the acceptor organelles contain proteins which are essential for targeted membrane fusion and protein transport (SNARE hypothesis). Membrane proteins of SSV analogues such as synaptophysin, synaptobrevin (v-SNARE) and synaptotagmin are key proteins of neurosecretion. The plasma membrane proteins syntaxin and SNAP25 (t-SNARE) are indispensible for this locking/fusion process. This study was done to identify the molecular components of LDCVs, SSV analogues and the SNARE-complex in neuroendocrine tumors. Immunohistochemical analysis using a panel of antibodies was done on file material from benign or low-grade malignant neuroendocrine tumors (n = 20) and high-grade malignant intermediate or small cell carcinomas (n = 27) of the gut, pancreas and lung. The statistical evaluation of our results indicate that the expression of all marker molecules of the regulated secretory pathway is significantly reduced in high-grade malignant carcinomas when compared to benign or low-grade malignant tumors. The reduction of the LDCV matrix protein chromogranin A and of the SSV membrane protein synaptobrevin is highly significant in high-grade malignant carcinomas, which may even loose these proteins. In contrast, the synthesis of synaptophysin and the t-SNARE-protein SNAP25 appears to be better maintained even in small cell carcinomas. We conclude that the immunohistochemical diagnosis of high-grade malignant neuroendocrine tumors should mainly be based on the identification of SSV- and SNARE-proteins, especially synaptophysin and SNAP25. These marker molecules of the regulated secretory pathway are valuable tools for the diagnosis and classification of neuroendocrine tumors and contribute to the understanding of cellular differentiation pathways.