Evidence for the existence of neuroendocrine (NE) differentiation in non-small cell lung carcinomas (NSCLCs) is at present based on histochemical, ultrastructural, and immunohistochemical data. The aim of this study was to investigate the extent of NE differentiation in NSCLCs as revealed by mRNA analysis. Different techniques including immunohistochemistry (IHC), northern blot analysis (NBA), and reverse transcriptase-polymerase chain reaction (RT-PCR) were employed in parallel to reveal the panendocrine marker chromogranin A (CgA). The data were related to pathological, immunocytochemical (PGP 9.5, synaptophysin, Leu-7 and neuronspecific enolase), and prognostic indicators. Forty surgically resected cases of NSCLC (24 squamous cell carcinomas, 12 ordinary type adenocarcinomas, 3 bronchiolo-alveolar carcinomas, and 1 anaplastic large cell carcinoma), in which fresh frozen material was available for mRNA analysis, were collected. CgA immunoreactivity was present in five cases (12β’5 per cent), generally confined to a minority of the neoplastic cell population. By RT-PCR, CgA mRNA was found in 20 cases (50 per cent), including the five tumours positive by IHC. A statistically significant correlation was found between the two techniques. By NBA, no CgA mRNA expression was detected. Leu-7 immunoreactivity was present in 15 per cent of cases, NSE in 52β’5 per cent, synaptophysin in 10 per cent, and PGP 9.5 in 82β’5 per cent. In NSCLC, no correlations were found between CgA production, as detected by IHC or RT-PCR methods, and the histological type, stage, grade and proliferative activity of tumours, or the disease-free interval. It is concluded that CgA gene expression can be revealed in NSCLC at both mRNA and protein levels and that RT-PCR is a valuable tool for identifying NE differentiated NSCLCs. Our data suggest that NE differentiation does not represent an independent prognostic factor in surgically resected NSCLCs. 1998 John Wiley & Sons, Ltd.