Objective To evaluate the clinical efficacy of entecavir (ETV) or adefovir dipivoxil (ADV) monotherapy in treatment of HBeAg-negative chronic hepatitis B (CHB) patients with mildly elevated ALT.Methods One hundred and seven HBeAg-negative CHB patients with ALT elevated by 1-2-fold of upper limit of normal (ULN) were enrolled in this prospective study.Sixty patients were assigned to receive ETV monotherapy and 47 patients to receive ADV monotherapy for at least 96 weeks.The ALT and HBV DNA levels were measured every 3 months.The liver biopsy was performed in 35 patients prior to therapy.Drug resistance and adverse reactions were documented.Results Four cases in ETV group and 2 cases in ADV group were lost in follow-up.Among 35 patients with liver biopsy,30 (86％) cases had significant fibrosis (stage 2-4) or inflammation (grade 2-4).At weeks 96,serum ALT was normalized in 67％ (30/45) cases of ADV group,and 95％ (53/56) cases of ETV group (x2 =13.33,P ＜ 0.01) ; the proportion of patients with undetectable HBV DNA in ADV and ETV groups was 78％ (35/45) and 100％ (56/56) respectively (x2 =13.81,P ＜ 0.01).No drug resistance occurred in ETV group,while 2 patients in ADV group were found with virological breakthrough and were confirmed to be of variants associated with ADV resistance.No adverse reactions were observed in either group during the trial.Conclusion Present study suggests that most HBeAg-negative CHB patients with mildly elevated ALT have significant fibrosis or inflammation and entecavir monotherapy was more effective than adefovir dipivoxil monotherapy in treatment of the patients.