Results comparing the effectiveness of lamivudine used as monotherapy or in combination with interferon-alpha (IFN-alpha) in the treatment of chronic hepatitis B are not conclusive. This study compared the effects of IFN-alpha alone or in combination with lamivudine for the treatment of hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B. Participation of patients in the IFN-alpha monotherapy and combination groups was randomized to a 1:1 ratio. Twenty seven HBeAg-negative patients with chronic hepatitis B received IFN-alpha (13 patients) at 9 million units 3 times weekly for 24 weeks or IFN-alpha at 9 million units 3 times weekly for 24 weeks plus lamivudine 100 mg/day (14 patients) daily for 1 year. Hepatitis B virus (HBV) DNA was measured quantitatively by real-time polymerase chain reaction at 0, 6, 12 and 18 months after the start of treatment. Sustained virologic response was defined as non-detectable serum HBV DNA 72 weeks after starting treatment. Sustained biochemical response was defined as normalization of alanine aminotransferase (ALT) values 72 weeks after starting treatment. The baseline characteristics of the 2 treatment groups were similar with respect to age, gender, ALT, HBV DNA levels and histologic diagnosis. Sustained biochemical responses were found at week 72 in 7 patients in each group (54% with IFN-alpha monotherapy and 50% with combination therapy) [p>0.05]. Sustained virologic responses were found at week 72 in 5 patients (38%) in the monotherapy and 7 patients (50%) in the combination therapy group (p>0.05). Combination therapy was not superior to IFN-alpha alone for the treatment of chronic hepatitis B. Combination treatment was associated with some disadvantages, such as additional cost. Lamivudine, on the other hand, may be more suitable for patients with cirrhosis, non-responders to IFN-alpha or in cases with contraindication for IFN-alpha.