Endogenous catecholamine release-inhibitory peptide catestatin has been associated with heart failure (HF). This subgroup analysis of our cohort of HF compared the different effects of catestatin as a predictor for cardiac outcomes in patients with HF with reduced (HFrEF), mildly reduced (HFmrEF) or preserved (HFpEF) ejection fraction. Plasma catestatin was measured in the HF patient cohort of 228 cases with a whole spectrum of ejection fraction. The cardiac deaths were analysed according to prespecified subgroups. Over a median follow-up of 52.5months, the association between plasma catestatin and cardiac death was different in patients with HFrEF, HFmrEF or HFpEF [hazard ratio (HR) 1.53, 95% confidence interval (CI) 0.99-2.37 and HR 2.73, 95% CI 1.56-4.75, respectively; interaction P=0.022]. Patients with HFmrEF/HFpEF were older and more likely to be female, with non-ischaemic cardiomyopathy and atrial fibrillation but lower levels of plasma B-type natriuretic peptide (BNP). Similar adverse cardiac events occurred in patients with HFmrEF/HFpEF as in HFrEF. Plasma catestatin was a better predictor for cardiovascular death in the HFmrEF/HFpEF patients [area under the receiver operating characteristic curve (AUC)=0.72, 95% CI 0.45-0.74] than in the HFrEF patients (AUC=0.59, 95% CI 0.587-0.849). The optimal cut point of plasma catestatin level of 0.86ng/mL predicted a 2.80-fold elevated risk for cardiac death in HFmrEF/HFpEF. Elevated plasma catestatin might be a more sensitive predictor for cardiac outcome in patients with HFmrEF/HFpEF than in HFrEF.