TGF‐β is a potent inducer of epithelial‐to‐mesenchymal transition (EMT), a process involved in tumour invasion. TIF1γ participates in TGF‐β signalling. To understand the role of TIF1γ in TGF‐β signalling and its requirement for EMT, we analysed the TGF‐β1 response of human mammary epithelial cell lines. A strong EMT increase was observed in TIF1γ‐silenced cells after TGF‐β1 treatment, whereas Smad4 inactivation completely blocked this process. Accordingly, the functions of several TIF1γ target genes can be linked to EMT, as shown by microarray analysis. As a negative regulator of Smad4, TIF1γ could be crucial for the regulation of TGF‐β signalling. Furthermore, TIF1γ binds to and represses the plasminogen activator inhibitor 1 promoter, demonstrating a direct role of TIF1γ in TGF‐β‐dependent gene expression. This study shows the molecular relationship between TIF1γ and Smad4 in TGF‐β signalling and EMT.