BACKGROUND/AIMS: Add on adefovir (ADV) to ongoing lamivudine (LAM) has been recommended as a standard therapy for the treatment of LAM resistance. In the past, switch to ADV monotherapy was suggested as an option for the treatment of LAM resistance, leading to frequent development of ADV resistance. However, ADV monotherapy has been still used in LAM-resistant patients because of low cost in Korea. The aims of this study were to evaluate the virologic response and virologic breakthrough during adding on LAM in LAM-resistant patients receiving ADV monotherapy. METHODS: The study population comprised 99 patients with LAM-resistance. We divided them into 3 groups (Group 1: switch to ADV monotherapy, N=58, Group 2: add on ADV to ongoing LAM, N=25, Group 3: add on LAM to ADV monotherapy, N=16). HBV DNA levels were assessed at baseline and every 3 months during therapy. Serum HBV DNA levels were measured by bDNA assay or the COBAS TaqMantrade mark HBV test. RESULTS: The median treatment duration for group 1, group 2, and group 3 was 42.0, 20.6, and 31.8 (18.7 mon. of ADV+13.1 mon. of LAM) months, respectively. Cumulative rate of virologic breakthrough in group 1 was 5.2%, 19.0%, and 25.9% at 12, 24, and 36 months of treatment, respectively. Virologic breakthrough was not detected in group 2 and group 3 (p=0.016, group 1 vs. group 2 or 3). In group 3, median serum HBV DNA levels were 4.22 log10 copies/mL prior to LAM administration. Median serum HBV DNA changes from baseline (log10 copies/mL) were -0.91, -1.93, -1.87 and -1.74 at week 12, 24, 36 and 48, respectively. CONCLUSIONS: Later add on LAM to ADV monotherapy prevented the development of ADV resistance in patients with LAM resistance effectively, comparable to ADV add on to continuing LAM therapy.