Objective To investigate the correlation of serum ferritin (SF), transferrin saturation (TSAT) and homocysteine (Hcy) with erythropoietin (EPO) hyporesponsiveness in chronic heart failure (CHF) patients with anemia and its clinical significance. Methods A total of 252 CHF patients with anemia admitted in our hospital from April 2019 to December 2021 were enrolled and divided into low response group (n=68) and non-low response group (n=184) according to their EPO response. The relevant factors affecting EPO response were analyzed and the value of SF, TSAT and Hcy was assessed in prediction for EPO hyporesponsiveness. SPSS statistics 24.0 was used to analyze the data. Student′s t test and Chi-square test were used to for comparison between groups depending on data type. Spearman correlation analysis was applied to analyze the correlation of SF, TSAT and Hcy with New York Heart Association (NYHA) classification of cardiac function. Multivariate logistic regression model was employed to analyze the influencing factors of EPO hypo responsiveness. Receiver operating characteristic (ROC) curve was used to analyze the prediction role of SF, TSAT and Hcy for EPO hyporesponsiveness.Results Statistical difference was observed in NYHA classification between the low response group and the non-low response group (P<0.05). The low response group had significantly lower SF and TSAT levels but higher Hcy levels when compared with the non-low response group (P<0.05). SF and TSAT were negatively correlated with NYHA classification (r=-0.742, -0.751; P<0.001), and Hcy was positively correlated with the classification (r=0.800; P<0.001). NYHA class IV, hemoglobin, SF, TSAT and Hcy were factors influencing EPO hyporesponsiveness (P<0.05), and the area under the curve value of SF, TSAT and Hcy combined together for predicting EPO hyporesponsiveness was 0.909, greater than that of SF (0.733), TSAT (0.752) and Hcy (0.724) alone. Its predictive sensitivity was 94.12%, and its specificity was 71.74%.Conclusion SF, TSAT and Hcy are related to EPO hyporesponsiveness and cardiac function in CHF patients with anemia. Combined detection of the three indicators can be used as a predictor for EPO responsiveness and provide reference for clinical treatment.