ZNF580 (gene ID 51157), a novel gene encoding a C2H2 (Cys2‐His2) zinc‐finger transcription factor, may be involved in the maintenance of vascular endothelium homoeostasis. To investigate the physiological role of the transcription factor ZNF580, we screened human foetal brain cDNA library with a yeast two‐hybrid system and identified 14 proteins that interact with ZNF580. The interaction between ZNF580 and Smad2 was confirmed by co‐immunoprecipitation. Co‐localization between endogenous ZNF580 and Smad2 was mainly found in the nuclei of EA.hy926 endothelial cells with immunofluorescence and confocal microscopy. Our results suggest that ZNF580 is a binding partner of Smad2 and is involved in the signal transduction of the TGF‐β (transforming growth factor‐β) signalling pathway, which provides a basis for additional research to investigate the role of ZNF580 in the maintenance of vascular endothelium homoeostasis and the onset of atherosclerotic diseases.