We have previously shown that expression of gp 200‐MR6, a molecule that is functionally associated with the interleukin‐4 receptor (IL‐4R), is lost from breast carcinoma cells as malignancy increases. Here we have analysed a series of colorectal carcinoma cell lines and show a similar decrease with increasing malignancy. Moreover, analysis of the HRA‐19 cell line, which can exhibit a poorly or a well‐differentiated phenotype according to culture conditions, shows that gp200‐MR6 is weakly expressed on the former but strongly expressed on the latter. Functional analysis using either IL‐4 or monoclonal antibody (MAb) MR6 and the well‐differentiated cell line SW1222 revealed that MAb MR6 acts as an agonist for IL‐4, with both reagents causing a dose‐dependent inhibition of cell division, but greatly enhancing the glandular differentiation of SW1222 in three‐dimensional collagen gels. These observations suggest that the gp200‐MR6 molecule may act as the product of a tumour suppressor gene and that its loss may be a primary event in tumourigenesis. Int. J. Cancer 71:605‐611, 1997. © 1997 Wiley‐Liss, Inc.