〔Abstract〕 Objective To explore whether baseline plasma fibroblast growth factor 21 (FGF21) levels are associated with treatment outcomes in patients with dilated cardiomyopathy (DCM) who are overweight/obese. Methods A prospective study included 217 patients with DCM and overweight/obese (24 kg/m2≤ BMI < 40 kg/m2). All patients received standardized heart failure medication. Baseline FGF21 levels were measured at enrollment. Left ventricular ejection fraction (LVEF), NYHA functional class, and B-type natriuretic peptide changes were assessed during a 12- month follow-up. Patients were divided into an effective group (n=155) and an ineffective group (n=62) based on the criteria for treatment effectiveness (meeting≥2 criteria: LVEF improvement≥10%, NYHA functional class improvement≥1, and BNP decrease≥50%). Spearman correlation analysis, Logistic regression, and ROC curve analysis were employed to evaluate the association of FGF21 with therapeutic efficacy and major adverse cardiovascular events. Results Baseline FGF21 levels in the invalid group were higher than those in the valid group (median: 244.65 pg/mL vs 198.40 pg/mL, P<0.001). FGF21 was positively correlated with follow-up BNP (r=0.184, P<0.05) and negatively correlated with follow-up LVEF (r=-0.140, P<0.05). Multivariate Logistic regression analysis showed that FGF21 was an independent risk factor for poor treatment response (P<0.001). The area under the receiver operating characteristic curve (ROC) was 0.90, with the optimal cutoff value being 205 pg/mL. The high FGF21 group (≥205 pg/mL) had a higher risk of major adverse cardiovascular events (P<0.001). Conclusion Baseline FGF21 elevation is independently associated with reduced treatment response and increased risk of MACE in DCM patients with overweight/obesity, serving as a prognostic biomarker for predicting treatment efficacy, which facilitates risk stratification and personalized therapy.