BACKGROUND: The clinical significance of β1AR-AAb (β1-adrenergic receptor autoantibody) subclasses, particularly IgG3 (immunoglobulin G subclass 3), in contemporary populations with HF (heart failure) remain unclear, especially in relation to β-blocker therapy and HF phenotype. METHODS: In this single-center prospective cohort study, we enrolled 408 consecutive patients hospitalized for acute decompensated HF. β1AR-AAbs and IgG subclasses were measured using enzyme-linked immunosorbent assay. Patients were classified into IgG3-positive, non-IgG3-positive, and negative groups. The primary end point was all-cause mortality within 2 years, and the secondary end point was a composite of all-cause death and HF rehospitalization. Multivariable Cox hazards models were used to assess associations, adjusting for clinical covariates, with subgroup analyses by HF phenotype (HF with reduced ejection fraction versus HF with preserved ejection fraction) and β-blocker use at discharge. RESULTS: β1AR-AAbs were detected in 34% of patients, with similar prevalence across HF phenotypes. IgG3-β1AR-AAb positivity was associated with higher in-hospital mortality (11%) and increased risk of all-cause death (adjusted hazard ratio [HR], 2.13 [95% CI, 1.14-3.99], P=0.018) and the composite end point (HR, 1.94 [95% CI, 1.19-3.14], P=0.008). These associations were observed primarily in patients not receiving β-blockers at discharge, with significant interaction between IgG3-β1AR-AAb and β-blocker use. Exploratory analyses suggested that these associations were more apparent in HF with preserved ejection fraction. CONCLUSIONS: IgG3-β1AR-AAb positivity was associated with adverse outcomes in acute HF, particularly among patients not treated with β-blockers. These findings suggest a potential role of IgG3-β1AR-AAb as a treatment-responsive biomarker, although prospective studies are needed.