Objective: In the heart, IGF-1 regulates cardiomyocyte hypertrophy, proliferation, metabolism, and protection from cell death. After injury, fibroblasts transdifferentiate into contractile myofibroblasts for tissue remodeling. However, the role of IGF-1 signaling in cardiac fibrosis has not been directly evaluated in vivo. Methods: Here, we examined injury-induced cardiac fibrosis in fibroblastspecific inducible Cre-expressing mouse lines with selective deletion of the IGF-1 receptor (IGF-1R). Results: Mice deficient fibroblast-specific IGF-1R exhibited enhanced cardiac interstitial fibrosis and significantly more severe cardiac dysfunction following 7-day angiotensin II/phenylephrine (Ang II/PE) infusion compared to wild-type mice. Ang II/PE increased TGF-β signaling, as shown by the increased phosphorylation of SMAD2, an activating SMAD, while Ang II/PE-induced SMAD2 activation was markedly accelerated in fibroblast-specific IGF-1R KO mice. In vitro studies with adult primary rat cardiac fibroblasts revealed that Ang II induced the expression of α-SMA, which was completely blocked by co-incubation with IGF-1. Conclusion: These results demonstrate IGF-1 negatively regulates cardiac fibrosis by attenuating Ang II induced transdifferentiation of fibroblasts to myofibroblasts and may represent a novel therapeutic approach against fibrotic cardiac remodeling.