The transmembrane mucin, MUC1, is overexpressed on many human carcinoma cells, increasing their metastatic potential through decreased cell-cell and cell-matrix adhesion. These cellular changes are mediated both through the altered physical properties of the mucin itself and through the role of the MUC1 cytoplasmic domain as a signaling molecule. The epidermal growth factor receptor (EGFR) is also overexpressed in many cancers and both it and MUC1 constitute important therapeutic targets. In the present study, expression of MUC1 was downregulated by treatment of KB carcinoma cells with a MUC1 small interfering RNA resulting in an inhibition of cell proliferation and colony formation and an increase in cell-cell aggregation. Surprisingly, suppression of MUC1 also inhibited expression of EGFR at both the mRNA and protein levels whereas the reciprocal effect was not observed. These results demonstrate a role for MUC1 in the regulation of EGFR expression and suggest that MUC1 gene silencing may represent a novel therapeutic approach in the treatment of a variety of human cancers.