This study was designed to investigate the effect of low-dose nesiritide on renal function and major cardiac events in patients with acute decompensated heart failure following acute myocardial infarction. Sixty patients were randomized into nesiritide (loading dose 0.5 μg/kg, maintenance dose 0.0075 μg/kg/min) and nitroprusside groups. Compared with the nitroprusside group, the nesiritide group had a greater heart rate reduction (P < 0.05), higher 24 h urine volume (P < 0.001), and more significant alleviation in dyspnea (P < 0.001). The prevalence of hypotension in the nesiritide group was lower than in the nitroprusside group (7.4% vs 28.5%, P < 0.05). The nesiritide group had a greater reduction in serum noradrenaline, angiotensin II, aldosterone, endothelin, and N-terminal prohormone brain natriuretic peptide (all P < 0.01). The mean serum creatinine in the nesiritide group was reduced (109.4 ± 26.6 vs 102.8 ± 21.6 μmol/l, P < 0.01), whereas it remained unchanged in the nitroprusside group (106.8 ± 20 vs 106.0 ± 19.2 μmol/l, P > 0.05). The rehospitalization or mortality rate was similar between the two groups 3 months after the therapy (P > 0.05). We conclude that low-dose nesiritide is more effective in suppressing the activation of the sympathetic and renin-angiotensin systems. It also improves the clinical symptoms and enhances renal function, but its effect on hospital readmission or mortality rate needs further investigation.