Objective: To observe the efficacy and safety of de novo combination of Lamivudine(LAM) and Adefovir Dipivoxil (ADV) therapy counter to Entecavir (ETV) monotherapy in patients with chronic hepatitis B (CHB)- related compensated liver cirrhosis. Methods: Patients with chronic hepatitis B-related compensated cirrhosis who were initially treated with LAM and ADV for more than 1 year were randomly assigned to two groups, one half replaced with ETV monotherapy, and the other half continued LAM and ADV co-therapy. Liver biochemistry, renal biochemistry, estimated glomerular filtration rate, alpha-fetoprotein, HBV serology markers and serum HBV DNA were measured every 3 months. Urine β2-microglobulin was measured every 6 months And retinol binding protein, followed up for 3 years. The mean values of the two groups were compared with t-test, and the rate of comparison was analyzed by x2 test. Results: A total of 580 cases were collected, 290 cases were replaced with ETV monotherapy, the other 290 patients continued to LAM and ADV combination therapy. In the ETV group, the rates of HBV DNA negative conversion at 1 year, 2 years and 3 years were 77.6%, 84.5% and 94.5% respectively, while the HBV DNA negative conversion rates at 1, 2 and 3 years in the LAM and ADV combination groups were 69.3%, 73.4% and 80.3% respectively. Among them, the negative rates of HBV DNA in the second year and the third year were P < 0.05, the difference was statistically significant. The 3-year cumulative gene-resistant rate in the ETV group was 1.4%, while the combined treatment was as high as 8.6%, and the difference was statistically significant in the two groups. The estimated value of serum creatinine and glomerular filtration rate in ETV group was followed by 3 years, and the baseline level was maintained, in the same group, the serum creatinine was higher than baseline, and the estimated value of glomerular filtration rate decreased. The results showed that there were 6.2%, 12.1%, 22.1% and 0, 0.3%, 1%, respectively, in 1, 2 and 3 years for the group of consecutive treatment and the replacement of ETV Group. The estimated glomerular filtration rate decreased by more than 30% compared with the baseline. The difference was statistically significant; the proportion of serum creatinine in the 1 year, 2 years and 3 years of the combined treatment group was 1.7%, 4.5% and 6.6%, compared with the baseline rise of > 50 μmol/l, and the ETV group was replaced in the 1 year, The values of 2 and 3 years were 0,0,0.7%, of which the 2nd and 3rd years were statistically significant; the proportion of microalbuminuria and retinol-binding protein in patients with combined treatment group was also significantly higher than that of Β2-m ETV Group. Conclusion The initial combination of LAM and ADV therapy is inferior in terms of ETV monotherapy. Single therapy with ETV increase the rate of viral response, reduce the incidence of drug resistance, and also reduce the incidence of renal impairment in patients with chronic hepatitis B -related compensated liver cirrhosis.