Objective To compare the effect of levosimendan and milrinone on treatment of severe heart valve disease patients with postoperative low cardiac output syndrome. Methods Fifty-six severe heart valve disease patients with postoperative low cardiac output syndrome were selected, and the patients were divided into levosimendan group and milrinone group according to treatment method with 28 cases each. Both groups received symptom-relieved therapy, including cardiotonic, diuresis and other drugs. The patients in levosimendan group were combined with 24 h of continuous intravenous injection of levosimendan 0.05-0.20 μg/(kg·min) for 1 week, and the patients in milrinone group were combined with 24 h of continuous intravenous injection of milrinone 0.25-1.00 μg/(kg·min) for 1 week, in order to maintain mean arterial pressure ≥ 65 mmHg (1 mmHg=0.133 kPa). The cardiac output, cardiac index, left ventricular ejection fraction (LVEF), and the serum levels of lactic acid, creatinine, N-terminal pro brain natriuretic peptide (NT-proBNP) were compared between 2 groups. Results There were no statistical differences in cardiac output, cardiac index, LVEF, and the serum levels of creatinine, lactic acid, NT-proBNP before treatment between 2 groups (P>0.05). The cardiac output, cardiac index, LVEF, and the serum levels of creatinine, lactic acid and NT-proBNP after treatment in 2 groups were significantly better than those before treatment, and there were statistical differences ( P<0.05). There were no statistical differences in cardiac output, cardiac index and LVEF after treatment between 2 groups (P>0.05). The serum levels of creatinine, lactic acid and NT-proBNP after treatment in levosimendan group were significantly lower than those in milrinone group: (102.82 ± 21.31) μmol/L vs. (115.64 ± 58.73) μmol/L, (1.7 ± 1.4) mmol/L vs. (2.2 ± 1.0) mmol/L and (1 149 ± 515) ng/L vs. (1 321 ± 472) ng/L, and there were statistical differences (P<0.05). Conclusions Both the two drugs can significantly improve cardiac function in severe heart valve diseases patients with postoperative low cardiac output syndrome, while the levosimendan has more advantages in lowering serum creatinine, lactic acid value and NT-proBNP.