Currently, the best option for patients with hepatitis delta is interferon alpha therapy for at least one year. To evaluate the effect of the combination lamivudine–high-dose interferon alpha therapy, we first treated eight patients with chronic hepatitis delta infection with lamivudine for at least 24 weeks; then lamivudine was combined with a high dose of interferon alpha followed by a regular dose (9 MU tiw). Follow-up was 12 weeks. Virological, biochemical and histological features were evaluated for response to therapy. At baseline, all patients were HBsAg positive in serum and HDV RNA-(PCR)positive in plasma; HBV DNA was undetectable with the Digene Hybrid Capture assay (limit of detection 1.5 × 106 geq ml–1) in all cases. Transaminases were elevated in all patients; median ALT 68 (range 48–143) IU l–1. Seven of eight patients completed the course; one patient with a pre-existing sickle cell trait was withdrawn from the trial due to the development of a nephrotic syndrome. The HBsAg-concentration in serum decreased in two out of seven patients (29%). However, there was no significant decrease in the HBsAg-concentration in serum during treatment (median 3654 PEU l–1 (range 548–7684) to 5300 PEU l–1 (range 168–19639)). The drop of HDV RNA in plasma from baseline during treatment was not significant. Decrease of HDV RNA was observed in three out of seven patients (43%) (median 105 geq ml–1; range 103–106 to median 103 geq ml–1; range 102–107). Serum ALT did not change as reflected by a median of 68 IU l–1 (range 48–143) at start of therapy to 63 IU l–1 (range 20–171) at the end of therapy. At the end of treatment transaminases had normalised in one patient and decreased in three other patients (improvement in 57%). However, three of these four patients showed a rebound after withdrawal of therapy. The Histology Activity Index (HAI) indicated a drop from a median score of 7 (range 5–9) at baseline to 5 (range 3–8) at the end of treatment, but an increase in fibrosis from a median grade of 2 (range 1–3) at baseline to 3 (range 1–4) at the end of treatment was observed. In conclusion, this study does not yield support for the combination of an HBVsuppressor and 16 weeks of high-dose interferon for therapy aimed at eradicating the hepatitis delta virus.