Lamivudine (LAM) resistance is frequently associated with various types of genomic changes in hepatitis B virus (HBV)-DNA including YMDD mutations (rtM204V/I). We intended to examine the effects of these genotypic variants on the antiviral efficacy of adefovir dipivoxil (ADV) therapy. A total of 97 chronic hepatitis B (CHB) patients with YMDD mutants who had been treated with ADV for >12 months were analysed. Mutations of the entire polymerase domain of HBV were determined by direct sequencing. All the 97 patients had genotype C HBV associated with rtM204V/I mutations; 63 (65%) rtM204I, 27 (28%) rtM204V and seven (7%) both. The rtL80V/I and rtL180M variants were identified in 66 (68%) and 67 (69%) patients respectively. The rtM204I and rtM204V variants were strongly associated with rtL80V/I and rtL180M respectively (P<0.01). There was no difference in antiviral response at 12 months after ADV therapy between patients in relation to the type of YMDD mutation or the presence of rtL180M. However, interestingly, after ADV therapy for 12 months, patients with rtL80V/I achieved a much smaller reduction in serum HBV-DNA titre than those without it (mean, -3.43 vs. -4.43 log(10) copies/ml; P=0.018). In addition, patients with rtL80V/I had lower rates of undetectable HBV-DNA (20 vs. 26%), alanine aminotransferase normalization (70 vs. 81%) and HBeAg loss (16 vs. 26%) than those without it, although none of these differences was statistically significant. These results provide evidence that rtL80V/I variants of HBV may be associated with a poor antiviral response to ADV in CHB patients with YMDD mutants.