Abstract： Objective To compare the 96-week efficacy of de novo combination therapy with lamivudine ( LAM ) and adefovir dipivoxil (ADV) to that of optimization monotherapy for chronic hepatitis B (CHB).Methods A total of 155 CHB patients were collected from the First Affiliated Hospital of Anhui Medical University during 2007 and 2009.All patients were randomly assigned to LAM monotherapy group ( n =53 ),ADV monotherapy group ( n =50 ) or LAM with ADV combination group ( n =52 ) according to randomized digital table.The liver and kidney functions,HBV serum markers,and HBV DNA loads were tested every 24 weeks.If patients in LAM or ADV group had poor response or virological breakthrough,they were given optimized therapy with ADV or LAM at week 24,48 or 72.One-way ANOVA (normal distribution and homoscedasticity ) and non-parametric test (non-normal distribution ) were performed to compare measurement data among groups.The impact factors of early virological response were analyzed by binary Logistic regression method.Results At week 24,the complete virological responses in LAM group,ADV group,and LAM + ADV group were 66.0％ ( 35/53 ),34.0％ ( 17/50 ) and 90.4％ ( 47/52 ),respectively (x2 =35.282,P ＜ 0.01 ) ; while,at week 96 the complete virological responses in three groups were96.2％ (51/53),86.0％ (43/50) and 100.0％ (52/52),respectively (x2 =19.115,P＞0.05).At week 96,the cumulative recover rates of ALT in LAM group,ADV group,and LAM + ADV group were 86.8％ (46/53),82.0％ (41/50)and 94.2％ (49/52),respectively (x2 =3.613,P ＞0.05);however,the ALT levels in three groups were statistically different (x2 =11.195,P ＜ 0.01 ).At week 96,the HBeAg seroconversion rates in LAM group,ADV group,and LAM + ADV group were 31.3％ ( 10/32),20.7％ ( 6/29 ) and 38.7％ ( 12/31 ),respectively (x2 =2.313,P ＞ 0.05 ).Early virological response was not found in I patient in LAM group and 19 patients in ADV group; virological breakthrough occurred in 11 patients in LAM group and 1 patient in ADV group.All patients in LAM + ADV group had early virological responses and had no virological breakthrough.Logistic regression showed that complete virological response at week 24 was correlated with the baseline HBeAg,the initial treatment and HBV DNA load.Layered evaluation showed that there were significant differences in early complete virological responses among three groups for patients with positive HBeAg,HBV DNA ＞ 6.28 × 106 copies/mL and ALT ≤5 ×ULN (x2 =7.726,10.921 and6.100,P＜0.05 or ＜0.01) ; for those with HBV DNA ＞6.28 × 106copies/mL,complete virological response was not observed in ADV group treated for 24 weeks.Conclusion LAM combined with ADV has stronger antiviral activity,lower resistance rate and can improve liver function and virological response,especially for the patients with HBeAg-positive,high HBV DNA loads and ALT ≤5 × ULN.