Objective To determine the independent risk factors for chronic heart failure with preserved ejection fraction (HFpEF) in the elderly and investigate the correlation between HFpEF and serum neprilysin (NEP). Methods A total of 56 consecutive patients admitted in the cardiovascular ward of the healthcare center of our hospital from January 2014 to January 2017 were enrolled in this study. Thirty-one HFpEF patients served as HFpEF group. Another 25 non-heart failure patients who matched with the HFpEF group in age, gender, comorbidity and medication and hospitalized in the same period served as control group. Serum NEP level was tested in the 2 groups by enzyme-linked immunosorbent assay (ELISA), and the results and other parameters were compared between the 2 groups. SPSS statistics 16.0 was used to perform the statistical analysis. Data were analyzed by Student’s t test or Chi-square test as appropriate. Parametric and non-parametric test were performed by Pearson and Spearman correlation analysis, respectively. Binary stepwise backwards logistic regression analysis was carried out to assess the independent risk factors for HFpEF. Results Compared with control group, the HFpEF group had significantly higher serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level [(3857.7±618.7) vs (1960.3±331.4)ng/L, P=0.000], serum uric acid level [(363.34±147.56) vs (332.11±84.58)μmol/L,P=0.042], left atrial diameter [(44.29±7.34) vs (37.59±2.97)mm, P=0.007], and left ventricular end diastolic diameter [(54.43±8.41) vs (49.13±2.77)mm, P=0.013], while obviously lower serum NEP level [(0.82±0.33) vs (0.98±0.62)ng/ml, P=0.001]. Only NT-proBNP was the independent risk factor for HFpEF in this cohort (95%CI:1.000-1.004,P=0.037) after adjustment of the confounding variables. There was no correlations of serum NEP level with NT-proBNP level, NYHA class and echocardiographic parameters (all P>0.05). Conclusion NT-proBNP is an independent risk factor for HFpEF in the elderly. Serum NEP has no correlation with NT-proBNP, and shows limited predictive value for HFpEF.