BACKGROUND Pegylated interferon (PEG-IFN)-alpha monotherapy is the current standard of care for short-term antiviral treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We aimed to assess the safety and efficacy of PEG-IFN-alpha plus adefovir dipivoxil (ADV) versus PEG-IFN-alpha monotherapy for compensated HBeAg-negative CHB. METHODS A multicentre randomized controlled trial was performed in eight outpatient hepatology/infectious disease clinics in central Italy. A total of 60 patients (67% male and median age 48 years) with biopsy-proven HBeAg-negative compensated CHB (mean alanine aminotranferase [ALT] levels 3.3 +/-3x the upper normal limit and serum hepatitis B virus [HBV] DNA 5.8 +/-0.9 log(10) IU/ml) were randomized at baseline to receive PEG-IFN-alpha2a 180 microg/week plus ADV 10 mg/day or PEG-IFN-alpha2a monotherapy for 48 weeks. Post-treatment follow-up was for 24 additional weeks. The primary end point was sustained HBV DNA suppression defined as serum HBV DNA<2,000 IU/ml after 24 weeks of post-treatment follow-up. The secondary end point was ALT normalization at the end of follow-up. RESULTS At week 48, HBV DNA was undetectable in 20/30 (67%) in the combination group versus 11/30 (37%) patients in the monotherapy group (P=0.02). ALT normalization was achieved in 17/30 (57%) versus 10/30 (30%) patients, respectively (P=0.03). At week 72, sustained virological response was achieved in 7/30 (23.3%) in the combination group versus 6/30 (20%) patients in the monotherapy group (P=0.75); 5 (16%) patients in each group dropped out because of adverse events or non-compliance. CONCLUSIONS In HBeAg-negative CHB, combination PEG-IFN-alpha2a plus ADV for 48 weeks is safe and resulted in greater on-treatment efficacy than PEG-IFN-alpha2a monotherapy. No difference in sustained virological and biochemical response rates were observed between the two treatment regimens.