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Background Data concerning the outcome of lamivudine-resistant (LAM-R) chronic hepatitis B (CHB) patients with compensated cirrhosis under adefovir (ADV) treatment are limited. The aim of our study was to evaluate the medium term outcome of these, high-risk for fatal events, patients. Methods 31 LAM-R patients with compensated cirrhosis who had been treated with ADV monotherapy ( n = 8) or ADV plus LAM ( n = 23) for a mean of 27.6 months, were evaluated. Virological response (VR) was defined as HBV-DNA levels 4 copies/ml within the first year of treatment. Results Twenty-three patients (74.19%) achieved VR. Six patients (19.35%) developed ADV-related mutations (annual incidence 11%). Liver-related death, liver decompensation and hepatocellular carcinoma (HCC) were observed in 12.9%, 16.12% and 16.12% of patients, respectively. HCC (annual incidence 9.1%) was the main cause of liver decompensation (4/5, 80%) and of liver-related deaths (3/4, 75%). HCC development was not related to patients' age ( p = 0.440), HBeAg status ( p = 0.245), HBV genotype ( p = 0.598), baseline ALT levels ( p = 0.981), baseline viral load ( p = 0.464), VR ( p = 0.504) as well as emergence of ADV resistance ( p = 0.871). Conclusions ADV suppresses viral replication in more than 70% of LAM-R cirrhotic patients during the first year of treatment. Despite that, HCC is frequently observed in these high-risk patients, irrespective of virological response or emergence of ADV resistance.