BACKGROUND: There is hypothesis that endothelial function enhancement is strongly associated with better outcome and functional class improvement in heart failure with preserved ejection fraction (HFpEF) and heart failure with mid-range ejection fraction (HFmrEF) patients. Perindopril is the only angiotensin-converting enzyme inhibitor (ACEI) drug with proven positive effect on the endothelium in coronary artery disease (CAD) patients. In patients with HFpEF and HFmrEF, its impact is still unknown. The aim of this study was to assess perindopril's influence on endothelial dysfunction markers in these groups of patients. METHODS: We included 60 patients with HFpEF and HFmrEF. At the baseline, endothelial dysfunction biomarkers were measured by IFA and echocardiographic parameters (left atrial volume index (LAVI), ejection fraction (EF), left ventricular mass index (LVMI), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-diastolic volume (LVEDV)) were studied. In patients with no history of previous ACEI or angiotensin II receptor blockers (ARBs) therapy, perindopril was prescribed for 12 months. If patient was treated with ARB or ACEI drug other than perindopril before the study, after 48-h withdrawal period, previous drug was replaced by perindopril. RESULTS: After 12-month therapy with perindopril, E-selectin decreased from 57.25 to 46.05 ng/mL and from 56.55 to 47.6 ng/mL in HFpEF and HFmrEF patients, respectively (P < 0.05). Significant reductions from 0.99 to 0.76 pg/mL (P < 0.05) and from 1.08 to 0.97 pg/mL (P < 0.05) in endothelin-1 level were shown in patients with HFpEF and HFmrEF. CONCLUSION: The 12-month therapy with perindopril leads to LAVI reduction in HFmrEF patients and potential endothelial dysfunction markers decrease in HFpEF and HFmrEF patients.