Abstract: Objective To explore the clinical effect of low-dose methylprednisolone combined with lamivudine in the treatment of hepatitis B patients with nephrotic syndrome. Methods A total of 92 hepatitis B patients with nephrotic syndrome who were treated in Rugao People's Hospital from January 2020 to October 2021 were selected. According to the random number table method, they were divided into two groups (n=46):a control group and an observation group. Patients in both groups underwent symptomatic treatment, such as diuresis, blood pressure control, anticoagulation, and leflunomide tablets. Additionally, the control group was treated with lafimidine, while the observation group was administered with low-dose methylprednisolone combined with lafimidine. Both groups were compared for clinical effect, kidney function indicators (serum creatinine, blood urea, blood uric acid and 24 h urine protein), liver function indicators, including glutamic pyruvic transaminase (ALT) and glutamic oxaloacetic transaminase (AST), and hepatitis B virus (HBV)-DNA contents. Results The effective rate in the observation group was 91.3% (42/46), higher than 76.1% (35/46) in the control group (P<0.05). After treatment for 6 and 12 months, the observation group showed remarkable increases in the levels of serum creatinine, blood urea, blood uric acid and 24 h urine protein, compared with the control group (P<0.05). After treatment for 6 and 12 months, the levels of ALT and AST in the two groups were significantly lower than those before treatment (P<0.05), but there was no statistical difference between the two groups (P>0.05). The HBV replication of patients during the medication period was monitored and the results showed that both groups presented a decreasing tread in HBV-DNA contents from before treatment to postoperative 1, 3, 6, 9 and 12 months, but no statistical difference was found between the two groups (P>0.05). Conclusions Low-dose methylprednisolone combined with lamivudine has a significant clinical effect in the treatment of hepatitis B patients with nephrotic syndrome, which can effectively improve liver and kidney functions without significantly increasing HBV replication.