There is considerable debate about whether the mucous neck cell (MNC) in the mucosa of the gastric corpus is merely a transit cell population, intermediate between gastric stem cells and the differentiated zymogenic (chief or peptic) cell lineages, or has distinct functions of its own. To cast light on these possibilities, the secretory phenotype of the MNC has been examined. Archival gastric body samples from non-ulcer dyspepsia biopsies and gastrectomies performed for peptic ulcer disease were stained with antibodies to the trefoil peptides TFF1/pS2 and TFF2/SP, pancreatic secretory trypsin inhibitor (PSTI), epidermal growth factor (EGF) and its receptor (EGFR), and to the MUC1 gene product--HMFG2. Human MNCs express PSTI, TFF1/pS2, TFF2/SP, and EGF proteins, while rat MNCs express TFF2/SP; the mucin contained in the MNCs is diastase/periodic acid Schiff (D/PAS)-positive and stains with human milk fat globulin (HMFG2). The canaliculi but not the cytoplasm of adjacent parietal cells were also decorated focally by D/PAS, by HMFG2, and by antibodies to TFF2/SP and TFF1/pS2. These findings favour the hypothesis that MNCs have a defined phenotype and are thus a separate and distinct cell lineage, secreting a number of luminally-active peptides which protect the gastric mucosa, and in particular the adjacent parietal cells, from the effects of secreted gastric acid. Moreover, a considerable degree of similarity in secretory profile is noted between MNCs and the so-called 'reparative lineages' in the gut--the ulcer-associated cell lineage (UACL) and hyperplastic polyp epithelium. If, on the other hand, the MNCs are indeed a transit population differentiating into zymogenic or peptic cells, then it is clear that having differentiated into one secretory phenotype producing a range of peptides, the MNC then proceeds to differentiate into a cell with a totally different secretory phenotype, a phenomenon unique in gastrointestinal cell lineage relationships.