We studied the long-term efficacy of adefovir dipivoxil (ADV) treatment in 42 HBeAgnegative patients with chronic hepatitis B (CHB) who had developed genotypical lamivudine (LAM) resistance with virological and clinical breakthroughs under long-term LAM treatment. Patients were allocated in 2 treatment groups. In the first (n ‫؍‬ 14), LAM was switched to ADV monotherapy whereas in the second (n ‫؍‬ 28) ADV was added to LAM. The two groups did not differ in patients' characteristics, all of them having HBV genotype D infection with the precore stop codon mutation. Within 12 months from start of ADV treatment, serum HBV DNA became nondetectable and ALT normalized in 71% and 90% of patients, respectively, with no difference between the 2 arms. Patients with baseline HBV DNA levels less than 10 7 copies/ml experienced a significantly earlier and more frequent decline in serum HBV DNA to nondetectable levels as compared with patients with greater than 10 7 HBV DNA copies/ml at baseline (P ‫؍‬ 0.0013) This response has hitherto been maintained (median treatment duration 40 months) in all patients with ADV added to LAM, whereas virological and biochemical breakthroughs due to development of ADV signature resistance mutations occurred in 3 of 14 patients (21%) on ADV monotherapy 15 to 18 months from start of treatment (P ‫؍‬ 0.0174). Conclusion: Adding ADV to LAM in HBeAgnegative CHB patients with LAM resistance effectively suppresses HBV replication in most of them and induces biochemical remission that can be maintained in all of them at least for 3 years without any evidence of development of resistance to ADV. (HEPATOLOGY 2007;45: 307-313.)See Editorial on Page 266 C hronic infection with the hepatitis B virus (HBV) represents a global health problem, being a major cause of liver disease, morbidity, and mortality. Effective long-term treatment of chronic viral B liver disease improves significantly patients' survival and reduces the risk of development of major complications. 1 Longterm nucleos(t)ide analog administration represents the first-line/first-choice therapy for most patients with chronic hepatitis B (CHB), particularly those with the hepatitis B e antigen (HBeAg)-negative type of the disease. [1][2][3][4][5] Lamivudine (LAM) is the first nucleoside analog approved in the treatment of CHB and, because of potency, safety profile, and relatively low cost, it has been and is still widely applied globally as first-choice therapy for CHB patients either HBeAg-positive or HBeAg-negative. 1 However, approximately 70% of CHB patients in long-term LAM therapy develop resistance to the drug within approximately 3 years of treatment and experience clinical relapses that may be severe and occasionally life threatening. 4,[6][7][8][9] Continuation of LAM therapy in patients who have developed virologic resistance is of no benefit to them. 7,10 LAM-resistant patients have been treated with adefovir dipivoxil (ADV) either in monotherapy or in combination with LAM without significant differences between the two regime...