Objective To compare recombinant human brain natriuretic peptide (rhBNP) with milrinone in their efficacy and safety in treating the elderly patients with acute exacerbation of chronic pulmonary heart disease (CPHD). Methods Totally 69 CPHD patients were retrospectively collected, who were admitted to Tianjin Hospital and the Third Central Hospital of Tianjin from January 2017 to December 2019, and they were divided into rhBNP group and milrinone group. Efficacy of the treatment was evaluated based on the change of heart rate (HR), 24-hour urine volume, brain natriuretic peptide (BNP), serum creatinine (SCr), pulmonary artery systolic pressure (PASP) and left ventricular ejection fraction (LVEF) before and after the treatment. SPSS statistics 17.0 was used for statistical analysis. Data comparison between two groups was perfomed using χ² test or t test depending on data type. Results The overall effective rate was 27(93.1%) in the rhBNP group and 29(72.5%) in the milrinone group with statistically significant difference (χ²=4.667, P=0.031). After treatment, the HR, BNP, SCr and PASP decreased, and the LVEF and 24-hour urine volume increased in both groups, the differences being statistically significant (all P<0.05). The comparison between two groups showed rhBNP outperformed milrinone in reducing BNP and PASP, improving LVEF, and increasing the 24-hour urine volume with significant differences (P<0.05). Nausea and vomiting, ventricular arrhythmia and other adverse reactions occurred in 3 (7.5%) patients in the milrinone group, and hypotension occurred in 2 patients in the rhBNP group, while the difference not being statistically significant (P>0.05). All patients with adverse reactions got improvement after dosage adjustment and symptomatic treatment, and no serious adverse outcomes occurred. Conclusion Both rhBNP and milrinone have obvious efficacy and safety in the elderly CPHD patients with acute exacerbation, and rhBNP is more effective than milrinone.