We have previously shown that expression of gp200-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.