Aims: Olfactomedin 4 is a useful marker for stem cells in the intestine and is an independent prognostic molecule for survival in patients with colorectal cancer (CRC). Claudin-18, a component of tight junctions, correlates with poor survival in patients with CRC and is associated with the gastric phenotype. We investigated the possible usefulness of these molecules in serrated neoplasia of the colorectum. Methods and results: We performed immunohistochemical analysis of colorectal polyps, including hyperplastic polyps (HP), sessile serrated lesions (SSL), traditional serrated adenomas (TSA) and conventional adenomas (CA). We also investigated the association between expression of these molecules and clinicopathological parameters in serrated adenocarcinoma (SAC) and non-SAC of the colorectum. Olfactomedin 4 expression was not detected or was decreased in SSL compared with the other polyp types. Claudin-18 expression was higher in SSL than in the other types. Similarly, positivity for olfactomedin 4 in SAC was significantly lower than that in non-SAC, and positivity for claudin-18 in SAC was significantly higher than that in non-SAC. Furthermore, claudin-18-positive SAC showed more advanced N grade and stage than claudin-18-negative SAC. Conclusions: Reduced expression of olfactomedin 4 and ectopic expression of claudin-18 might be useful markers in the differential diagnosis of serrated polyps. © 2013 Blackwell Publishing Ltd.