Objective To explore the relationship between serum miR-520e, miR-146a and clinicopathological parameters, prognosis in elderly patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods A total of 95 patients with HBV-related HCC and 100 patients with HBV in the hospital were enrolled as observation group and control group from February 2018 to February 2021. The levels of serum miR-520e and miR-146a in both groups were detected by real-time polymerase chain reaction (RT-PCR). The differences in the two indexes between the two groups and among patients with different pathological characteristics in observation group were compared. The 1-year progression-free survival curves in HCC patients with different levels of miR-520e and miR-146a were drawn. Results The levels of serum miR-520e and miR-146a in observation group were lower than those in control group (P<0.05). In HCC patients, levels of serum miR-520e and miR-146a in patients with lesion ≥3cm, cancer thrombus, lymph node metastasis and TNM staging at stage III-IV were significantly lower than those with lesion <3cm, without cancer thrombus or lymph node metastasis, and with TNM staging at stage Ⅰ-Ⅱ (P<0.05). In observation group, patients with miR-520e level lower or higher than the average were enrolled as low-expression miR-520e group and high-expression miR-520e group. In observation group, patients with miR-146a level lower or higher than the average were enrolled as low-expression miR-146a group and high-expression miR-146a group. The results of curves analysis showed that 1-year progression-free survival in patients with high expressions of miR-520e and miR-146a was significantly better than that with low expressions (P<0.05). Conclusion The levels of serum miR-520e and miR-146a in patients with HBV-related HCC are significantly lower than those in HBV patients. In patients with HBV-related HCC, there are significant differences in clinicopathological characteristics and prognosis among patients with different levels of serum miR-520e and miR-146a