Background: interferon-α is able to induce a sustained inhibition of hepatitis B virus replication in about 30–40% of patients with chronic hepatitis B. There is evidence that non-steroidal antiinflammatory drugs can enhance the synthesis of antiviral proteins induced by interferon-α, Aim: to evaluate the efficacy and tolerability of combined therapy with interferon-α plus indomethacin in HBeAg and HBV-DNA positive patients affected by chronic active hepatitis non-responders to a previous interferon-α treatment. Methods: after six months of retreatment with interferon-α (6 MU thrice weekly) six patients were enrolled, without stopping the therapy, to receive interferon-α (with the same schedule) plus indomethacin (25 mg orally twice daily) for an additional six month course. Results: at the end of treatment and after six months of follow-up alanine transaminase normalization was seen in three (50%) and four (66.7%) patients, HBV-DNA loss in one (17%) and three (50%), serum conversion in one (17%) and two (33%), respectively. The combined therapy was well tolerated and no indomethacin side-effects were observed. The treatment was stopped in one patient after 4 months because of a remarkable increase of alanine transaminase levels, and in another after five months because of hyperthyroidism occurrence. Conclusions: the results of this study, even if obtained in a small number of patients, are encouraging and suggest a randomized controlled trial to be confirmed.