The aim of this study was to investigate genotoxic effects of lamivudine (an analogue of cytidine) using in vitro sister chromatid exchange (SCE), chromosome aberration (CA), and micronucleus (MN) tests in human peripheral lymphocytes. The cells were treated with 75, 100, 125, and 150 mu g/ml concentrations of lamivudine (roughly 30-60 times higher than plasma levels achieved in patients receiving this drug) for two (24- and 48-hr) treatment periods. Lamivudine induced SCEs at the highest concentration (150 mu g/ml) in the 24-hr treatment, and at 125 and 150 mu g/ml in the 48-hr treatment, when compared to the solvent control. During both treatment periods, structural chromosome aberrations were significantly increased at 100, 125, and 150 mu g/ml lamivudine concentrations. However, the increases of SCEs (22%) and CAs (50%) were weak. In addition, lamivudine reduced both the proliferation index (PI) and the mitotic index (MI) significantly at all concentrations for the two treatment periods. The MI was reduced by lamivudine in a dose-dependent manner during both the 24- and 48-hr treatment periods. In contrast, the PI was reduced by lamivudine only during the 48-hr treatment period. A weak but significant increase in MN formation was observed following lamivudine treatment at 100, 125, and 150 mu g/ml for 48 hr, but no significant increase in micronuclei were observed following 24-hr treatment. In conclusion, lamivudine has a weak genotoxic effect at elevated doses on human peripheral lymphocytes.