The transforming growth factor (TGF-β)-inducible early gene (TIEG1), a member of the Sp1/Krüppel-like family of transcription factors, plays an important role in regulating cell growth, differentiation, and apoptosis in many human diseases, including breast cancer, osteoporosis, and atherosclerosis. However, little is known about the role of TIEG1 in the heart. In this study, we investigated the role of TIEG1 in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and its underlying mechanism. Our results showed that TIEG1 expression was downregulated in Ang II-induced hypertrophic cardiomyocytes. Gene silencing of TIEG1 by RNA interference upregulated cellular surface area and ANF and BNP messenger RNA levels, whereas TIEG1 overexpression inhibited the expression of those genes. Mechanistically, TIEG1 could inhibit the expression and transcriptional activity of transcription factor GATA4 in cardiomyocytes, which was recognized as an important factor mediating cardiac gene transcription. In summary, our data disclose a novel role of TIEG1 as an inhibitor in Ang II-induced hypertrophic cardiomyocytes through GATA4 signal pathway.