Objective To compare the 144-week efficacy of de-novo combination therapy with lamivudine (LAM) and adefovir dipivoxil (ADV) to that of optimize combination for chronic hepatitis B (CHB) patients.Methods A total of 83 cases with CHB were divided into 3 groups:the de-novo combination group (group A,28 cases),after 24-week mono-therapy to optimize combination group (group B,32 cases),after 48-week mono-therapy to optimize combination group(group C,23 cases).The virological,serological,biochemical indicators at baseline,week 24,48,96 and 144 were detected respectively.The gene resistance mutations of of HBV P region were analyzed for the patients whose HBV DNA were still positive (HBV DNA≥ 103 copies/mL) at week 96,144,respectively.Data of 3 groups were analyzed by the pharmacoeconomics cost-effectiveness analysis.Results HBV DNA negative conversion rates in 3 groups after 96-week therapy were 92.9％,90.6％,87.0％.There were no significant differences among 3 groups (x2 =0.509,P ＞0.05); HBV DNA negative conversion rates in 3 groups after 144-week therapy were 96.4％,93.8％,91.3％,and the differences among them were not statistically significant(x2 =0.590,P ＞ 0.05).There was 1 patient with virologic breakthrough at 144-week treatment in group A.The mutation sites in HBV P genes were L180M and M204V.HBeAg-positive patients with seroconversion rates in 3 groups after 96-week therapy were 27.8 ％,19.2％,35.7 ％,and the differences were not statistically significant (x2 =1.340,P ＞ 0.05).The seroconversion rates in 3 groups at week 144 were 38.9％,30.8％,42.9％,and the differences were not statistically significant (x2 ＝ 0.364,P ＞ 0.05).The ALT normalization rates in 3 groups at week 96 were 94.1％,90.9％,88.9％,and the differences were not statistically significant (x2 =0.303,P ＞ 0.05) ; The ALT normalization rates in 3 groups after 144-week therapy were 100.0 ％,95.5 ％,94.4％,and the differences were not statistically significant(x2=0.911,P ＞ 0.05).The cost-effect analysis showed that the initial combination group was superior to the optimize combination group.Conclusions The effects of virology negative conversion rate,seroconversion rate,ALT normalization rate and reduction the incidence of drug resistance in LAM + ADV de-novo combination therapy and optimized combination therapy are good,but optimized combination therapy is more economic than de-novo combination therapy,so optimized combination therapy can be recommended for use.