There are data in the literature that suggest a close relationship between the expression of CK20 and CDX2, K-ras mutations, and goblet cell morphology. The present study has examined these factors in a cohort of 264 non-small cell lung cancers. Thirteen of 212 adenocarcinomas expressed CK20; 29 expressed CDX2; K-ras mutation was identified in 28; and goblet cell features were present in 19. These four factors correlated with each other in a complex way and therefore a logistic regression model was constructed. Significant correlations were found between CK20 and CDX2 expression, and between K-ras mutation and goblet cell morphology, and there was a marginal correlation between CDX2 immunoreactivity and goblet cell morphology. These four features have also been commonly detected in colorectal, pancreato-biliary, and ovarian mucinous carcinomas, suggesting that these adenocarcinomas may be prototypical, independent of the organ of origin. Furthermore, as high and uniform expression of CDX2 was characteristic of metastatic colorectal cancer, weak and/or focal CDX2 expression should alert surgical pathologists to the possibility of primary lung adenocarcinoma, especially in the presence of goblet cell morphology. However, some lung adenocarcinomas may express CDX2 strongly: in this case, CK20 also tends to be positive. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.