AIMS: Oral sucrosomial iron (SI) combines enhanced bioavailability and tolerance compared to conventional oral iron along with similar efficacy compared to intravenous iron in several conditions associated with iron deficiency (ID). METHODS AND RESULTS: In this non-randomized, open-label study, we sought to evaluate prospectively the effects of SI on clinical parameters, exercise capacity and quality of life in 25 patients with heart failure (HF) with reduced ejection fraction (HFrEF) and ID, treated with SI 28 mg daily for 3 months, in comparison to 25 matched HFrEF controls. All patients were on optimal stable HF therapy. Patients were followed for 6 months for death or worsening HF episodes. There were no differences in baseline characteristics between groups. At 3 months, SI was associated with a significant increase in haemoglobin, serum iron and serum ferritin levels (all P ≤ 0.001) along with a significant improvement in 6-min walked distance and Kansas City Cardiomyopathy Questionnaire (all P < 0.01), even after adjustment for baseline parameters; these differences persisted at 6 months. Over the study period, there were no deaths, while 10 patients (20%) in total (four in the SI group and six in the control group), experienced worsening HF (odds ratio 0.51, 95% confidence interval 0.41-6.79, P = 0.482). Drug-associated diarrhoea was reported by one patient in the SI group and led to drug discontinuation; no other adverse events were reported. CONCLUSIONS: In this proof-of-concept study, SI was well tolerated and improved exercise capacity and quality of life in HFrEF patients with ID. Randomized studies are required to further investigate the effects of this therapy.