Objective To investigate the expression of miRNA-499 in peripheral blood of patients after cardiac surgery，and to confirm its predictive role on postoperative atrial fibrillation (POAF) and the response to amiodarone treatment. Methods Real-time quantitative polymerase chain reaction (RT-PCR) was used to detect the expression of miRNA-499 and its target mRNA in peripheral blood of 109 POAF patients and 96 non-POAF patients. At the same time，combined with amiodarone treatment，the prognosis was analyzed. Results miRNA-499 was significantly overexpressed in POAF patients （1.86 ± 0.35 vs. 2.77 ± 0.51，4.23 ± 1.37，P < 0.05）. Compared to non-POAF group，the expression of miRNA-499 was up-regulated in the amiodarone (-) group and the amiodarone (+) group，and the up-regulation of miR499 in the amiodarone (-) group was significantly higher than that in the amiodarone (+) group (2.77 ± 0.51 vs. 4.23 ± 1.37，P = 0.005). ROC curve analysis showed that miRNA-499 could be used as a potential biomarker of POAF amiodarone treatment response (AUC = 0.72，P = 0.006). Conclusion The increased expression of miRNA-499 may contribute to the clinical judgment of the occurrence of POAF after cardiac surgery，as well as predict the outcome and prognosis of amiodarone treatment on POAF patients.