Our previous reports have shown that microRNA-4651 is a potential early diagnostic and prognostic marker for hepatocellular carcinoma. We aimed to investigate whether microRNA-4651 modified postoperative adjuvant transarterial chemoembolization (pa-TACE) to improve the prognosis of hepatocellular carcinoma. A hospital-based retrospective study, including 302 patients with advanced-stage hepatocellular carcinoma who received tumor resection or tumor resection plus pa-TACE as an initial therapy, was conducted to assess the effects of microRNA-4651 on pa-TACE treatment. MicroRNA-4651 expression in tumor tissues was tested using the TaqMan-PCR technique. The sensitivity of tumor cells to doxorubicin (an anticancer drug used in pa-TACE procedure) was analyzed by the half-maximal inhibitory concentration (IC50). Upregulated microRNA-4651 expression in tumor tissues can improve the therapeutic response of patients with hepatocellular carcinoma on pa-TACE (hazard ratios [95% confidence intervals] = 0.32 [0.22-0.46] for death risk and 0.39 [0.28-0.56] for tumor-recurrence risk, respectively), but downregulated expression cannot. Functional analyses-displayed microRNA-4651 mimics decreased while its inhibitor increased the IC50 of tumor cells to doxorubicin (0.65 [0.61-0.69] versus 2.17 [1.98-2.37] µM). Cytochrome P450 2W1 was shown as a possible target of microRNA-4651. Additionally, dysregulation of microRNA-4651 also affected the clinical pathological features of hepatocellular carcinoma and was an independent prognostic factor for this cancer. Conclusion: These results indicate that increasing microRNA-4651 expression may be beneficial for pa-TACE in improving hepatocellular carcinoma prognosis.