Aim To observe the effects of erythropoietin （EPO） on neonatal rat cardiac fibrosis phenotypic switched into myofibroblasts induced by angiotensin Ⅱ （ AngⅡ ） and the association with possible signaling pathway （tran sforming growth factor-beta1（TGF-β₁）-TGF-β-activated kinase-1（TAK₁）-mitogen-activated protein kinase（p38MAPK））. Methods Cardiac fibroblasts were isolated from new-born Sprague-Dawley rats, and the cells were used to establish the model of fibrosis by Ang Ⅱ（10^-6 mol/L） in vitro. Then they were treated with EPO（20 kU/L），at the same time，they were treated with or without the p38MAPK inhibitor SB203580（15 μmol/L）. Immunohistochemistry was used to detect the intracellular protein expression of α-smooth muscle actin（α-SMA）. The mRNA levels of TGF-β₁ and p38MAPK was analyzed by quantitative real-time PCR. The protein expression of α-SMA，TGF-β₁, TAK₁, and p38MAPK and the phosphorylation of TAK₁ and p38MAPK were analyzed by Western blot. Results 20 kU/L of EPO can effectively inhibit AngⅡ-induced cardiac phenotypic switched into myofibroblasts, reduce the intracellular protein expression of α-smooth muscle actin （α-SMA）, and also can significantly suppress AngⅡ-induced upregulation of TGF-β₁, TAK₁, and p38MAPK expression and phosphrylation of TAK₁ and p38MAPK. The effects can be strengthened by SB203580. Conclusion EPO can effectively inhibit AngⅡ-induced cardiac phenotypic switched into myofibroblasts, reduce myocardial fibrosis, and can reduce the related signaling molecules mRNA and protein expression. Preliminary consideration of the EPO can inhibit myocardial fibrosis, reduce the process of ventricular remodeling through TGFβ₁-TAK₁-p38MAPK.