beta-Catenin binds to the cytoplasmic region of the type 1 membrane glycoprotein MUC1. In the current study, we utilized HEK293T cells expressing the full-length MUC1 protein, or a CD8/MUC1 fusion protein containing only the MUC1 cytoplasmic tail, to investigate the effects of beta-catenin binding to MUC1 on downstream beta-catenin-dependent events. Compared with HEK293T cells transfected with empty vector or CD8 alone, expression of the MUC1 cytoplasmic tail inhibited beta-catenin binding to E-cadherin, decreased translocation of beta-catenin into the nucleus, reduced activation of the LEF-1 transcription factor, and blocked expression of the cyclin D1 and c-Myc proteins. Furthermore, expression of MUC1 was associated with decreased cell proliferation, either in the context of the transfected HEK293T cells, or when comparing wild type (Muc1(+/+)) vs. knockout (Muc1(-/-)) mouse primary tracheal epithelial cells. We conclude that MUC1 inhibits cell proliferation through a beta-catenin/LEF-1/cyclin D1/c-Myc pathway.