In the interferon (IFN) treatment of chronic hepatitis B, there is no accepted definition of virological response as measured by highly sensitive HBV DNA assays. In the present study of 98 patients given IFN (10 MU/day for 1 week, then 10 MU TIW for 11 weeks) with or without prednisolone priming, a virological response was identified as log HBV DNA/mL below 6.0 (by Amplicor Monitor, Roche) 6 months post-treatment. At this time, 92% (33/36) of the sustained responders (SR) still had detectable viraemia with log HBV DNA/mL at 4.30 ± 0.15 (± SEM), as compared with 8.69 ± 0.097 in nonsustained responders. Pretreatment viraemia below a threshold at 500 million copies/mL was associated with higher chance of response (P=0.023). Prednisolone enhanced the sustained response (53% vs. 30%, P=0.025), and in particular end-of-treatment response (ETR, 50% vs. 10%, P < 0.0001). ETR was predictive for SR (P < 0.0001), especially when log HBV DNA/mL was < 4.0 (PPV=92%). The potential value of differentiating the therapy of chronic hepatitis B on the basis of viraemia levels, as measured by highly sensitive assays, should be further investigated.