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Background/Aims The susceptibility of adefovir-resistant hepatitis B virus (HBV) mutants is only reduced by 3–10-fold in in vitro studies, suggesting that virologic breakthrough and clinical deterioration are unlikely. The aim of this study was to describe the clinical course of patients with adefovir-resistant HBV infection. Methods Testing for adefovir-resistant mutations was performed on patients who had a suboptimal response or virologic breakthrough on adefovir. Adefovir-resistant mutations were detected using a line probe assay and direct sequencing of the HBV P-gene. Results Eight male patients with pre-existing lamivudine resistance or breakthrough (mean age 47±13 years) were found to have adefovir-resistant mutations rtA181V/T or rtN236T. Baseline median ALT was 66 IU/L (range, 27–1161) and median HBV DNA 7.9 log 10 copies/ml (range, 6–8.3). At the time of adefovir resistance (mean of 20±9 months), HBV DNA increased to ≥5 log 10 copies/ml in 7 patients. After detection of adefovir resistance, hepatic decompensation occurred in 2 patients, 1 of whom died. Salvage therapy with lamivudine, entecavir or tenofovir was given to 7 patients and a reduction in HBV DNA by ≥3 log 10 was seen in 3 patients. Conclusions In conclusion, adefovir resistance can be associated with significant viral rebound and hepatic decompensation which may be fatal.