In Xenopus, the maternal transcription factor VegT is necessary and sufficient to initiate the expression of nodal-related genes, which are central to many aspects of early development. However, little is known about regulation of VegT activity. Using maternal loss-of-function experiments, we show that the maternal homeoprotein, Tgif1, antagonizes VegT and plays a central role in anteroposterior patterning by negatively regulating a subset of nodal-related genes. Depletion of Tgif1 causes the anteriorization of embryos and the up-regulation of nodal paralogues nr5 and nr6. Furthermore, Tgif1 inhibits activation of nr5 by VegT in a manner that requires a C-terminal Sin3 corepressor-interacting domain. Tgif1 has been implicated in the transcriptional corepression of transforming growth factor-beta (TGFβ) and retinoid signaling. However, we show that Tgif1 does not inhibit these pathways in early development. These results identify an essential role for Tgif1 in the control of nodal expression and provide insight into Tgif1 function and mechanisms controlling VegT activity. Developmental Dynamics 237:2862–2873, 2008. © 2008 Wiley-Liss, Inc.