Lamivudine is an oral nucleoside analogue with strong antiviral activity against hepatitis B virus (HBV). In previous clinical studies, a course of lamivudine for 4-12 weeks induced a profound decrease in HBV viraemia with excellent tolerance, but data on histology have not yet been reported. We studied the liver histology of 13 patients with stable chronic HBV infection treated with 25 mg, 100 mg or 300 mg lamivudine daily for 6 months. All patients became HBV-DNA negative during treatment. The paired biopsies taken at entry and during treatment were scored by two independent observers, using the components of the histology activity index (HAI) and fibrosis (modified Knodell). The items scored were piecemeal necrosis, focal necrosis, confluent necrosis, portal inflammation and fibrosis. Before treatment, the biopsies yielded a mean HAI of 4.4 (+/- 0.8), which decreased to HAI 2.8 (+/- 0.5) during treatment. An analysis of the individual components of the classification system showed a significant decrease in piecemeal necrosis from a pre-treatment 1.4 (+/- 0.3) to 0.8 (+/- 0.1) during treatment (p = 0.02). Although a trend was found for the other components, it was not statistically significant, probably due to the number of pairs examined. In conclusion these results suggest that prolonged suppression of viral replication by lamivudine can improve liver histology. In contrast to previously published reports on alpha-interferon therapy, this study indicates that the improvement in liver histology with lamivudine is independent of HBe-seroconversion.