Indomethacin-induced G ₁ arrest and apoptosis of human colorectal cancer (CRC) cells is associated with a dose-dependent decrease in β-catenin protein levels. β-catenin plays a pivotal role in the WNT signalling pathway and its expression is frequently dysregulated at early stages of colorectal carcinogenesis. The objective of this study was to investigate the effect of indomethacin on catenin expression and downstream WNT signalling events in human CRC cells. β-catenin, γ-catenin and T-cell facter (TCF) target gene (c yclin D1 , c- MYC and PPARδ ) expression was studied following indomethacin treatment of SW480 and HCT116 cells. C yclin D1 was used as a model TCF target gene for analysis of β-catenin–TCF-4 DNA binding and trans -activation. Indomethacin treatment was associated with a specific decrease in β-catenin (but not γ-catenin) expression. Resulting TCF target gene expression was gene specific ( cyclin D1 , decreased; c- MYC , increased; PPARδ , no significant change) . Cyclin D1 promoter analysis revealed that indomethacin disrupted formation of a β-catenin–TCF-4–DNA complex. Indomethacin-induced G ₁ arrest and apoptosis is associated with specific β-catenin down-regulation in human CRC cells in vitro . Differential expression of TCF target genes following indomethacin treatment implies complex effects on multiple genes which play an important role in colorectal carcinogenesis.