We investigated the effects of transcriptional intermediary factor 1γ (TIF1γ) and SMAD4 on the proliferation and liver metastasis of colorectal cancer (CRC) cells through knockdown of TIF1γ and/or SMAD4 and knockdown of TIF1γ and/or restoration of SMAD4 expression. Furthermore, we examined TIF1γ and SMAD4 expression in human primary CRC and corresponding liver metastatic CRC specimens. TIF1γ promoted but SMAD4 inhibited the proliferation of CRC cells by competitively binding to activated SMAD2/SMAD3 complexes and then reversely regulating c-Myc, p21, p27, and cyclinA2 levels. Surprisingly, both TIF1γ and SMAD4 reduced the liver metastasis of all studied CRC cell lines via inhibition of MEK/ERK pathway-mediated COX-2, Nm23, uPA, and MMP9 expression. In patients with advanced CRC, reduced TIF1γ or SMAD4 expression was correlated with increased invasion and liver metastasis and was a significant, independent risk factor for recurrence and survival after radical resection. Patients with advanced CRC with reduced TIF1γ or SAMD4 expression had higher recurrence rates and shorter overall survival. TIF1γ and SMAD4 competitively exert contrasting effects on cell proliferation but act complementarily to suppress the liver metastasis of CRC via MEK/ERK pathway inhibition. Thus, reduced TIF1γ or SMAD4 expression in advanced CRC predicts earlier liver metastasis and poor prognosis.© 2023 Walter de Gruyter GmbH, Berlin/Boston.