Treatments that improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) have shown no benefits for those with heart failure with preserved ejection fraction (HFpEF). Our study aimed to investigate the impact of inhaled iloprost on myocardial performance during exercise in HFpEF.The study participants were enrolled from the ILO-HOPE trial (NCT03620526), a prospective randomized, double-blind, placebo-controlled study that was designed to investigate the effects of iloprost on cardiovascular haemodynamics during exercise in patients with HFpEF. Subjects were randomized 1:1 to inhalation of iloprost or placebo for 5 minutes. Two-dimensional transthoracic echocardiography with high temporal resolution was implemented to measure LV longitudinal strain, LV diastolic function and RV function both at rest and during supine exercise at 20-watt workload.Left ventricular global longitudinal strain (LV GLS) in response to exercise increased more in iloprost group (LV GLS, -24.96 ± 1.20 vs. -20.75 ± 3.00, p<0.001). Iloprost also resulted in greater increment of LV GLS during exercise (ΔLV GLS, +6.02 ± 1.39 vs. +3.44 ± 0.80, p<0.001). Moreover, iloprost use was associated with enhancement of LV diastolic function, RV systolic function and relief of pulmonary hypertension during exercise.In patients with HFpEF, inhaled iloprost favourably improved myocardial performance during exercise by increasing LV GLS reserve, decreasing LV diastolic filling load, and reducing stress-induced pulmonary hypertension and thereby improving RV systolic function. Larger studies are needed to validate the result and long-term benefits of iloprost in patients with HFpEF.