Background <p>Heart failure (HF) is a heterogeneous clinical syndrome affecting a growing global population. Due to the high incidence of cardiovascular risk factors, a large proportion of the Western population is at risk for heart failure. Oxidative stress and inflammation play a crucial role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). While previous studies have demonstrated an association between dysfunctional HDL and heart failure, the specific link between oxidized HDL and HF remains unexplored.</p> Methods <p>In this cross-sectional observational study, the antioxidant function of HDL was assessed in 366 patients with suspected heart failure. HFpEF assessment was conducted according to current guidelines. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function as assessed by increased HDL-lipid peroxide content (HDL_ox), normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDL_ox; no units). Results were expressed as median with interquartile range (IQR).</p> Results <p>Participants with HFpEF (<i>n</i> = 88) had 15% higher mean relative levels of nHDL_ox than those without heart failure (<i>n</i> = 180). Using a basic multivariate model adjusted for age, sex, eGFR and a full multivariate model (adjusted for diabetes, hypertension, atrial fibrillation, LDL cholesterol, hsCRP, and coronary artery disease), nHDL_ox was an independent predictor for HFpEF (<i>p</i> &lt; 0.05). An increase in 1-SD in nHDL_ox was associated with a 67% increased risk for HFpEF if compared with participants without heart failure (<i>p</i> = 0.02).</p> Conclusion <p>HDL antioxidant function is reduced in patients with HFpEF. Improving HDL function is a promising target for early heart failure treatment.</p>