Entecavir (Baraclude), a nucleoside analogue, is rapidly phosphorylated to the active intracellular 5'-triphosphate form that inhibits replication of hepatitis B virus (HBV). Oral entecavir is approved in the US, EU and several countries worldwide for the treatment of chronic HBV infection in adults (> or =16 years of age) with evidence of active viral replication and persistently elevated serum ALT and/or AST levels, and/or histological evidence of active disease. In several randomized, double-blind, multicentre trials, oral entecavir was an effective and generally well tolerated treatment in nucleoside-naive and lamivudine-refractory adult patients with chronic HBV infection, irrespective of whether patients were hepatitis B e antigen (HBeAg)-positive or -negative. Furthermore, it was more efficacious, associated with a lower risk of resistance, and more cost effective than lamivudine in these patient populations, with both drugs having a similar tolerability profile. In the EARLY trial, entecavir was significantly more effective than and as well tolerated as adefovir dipivoxil therapy in nucleoside-naive patients. In addition, in a double-blind, multicentre trial, entecavir plus lamivudine-based highly active antiretroviral therapy (HAART) was more effective than placebo plus lamivudine-based HAART in patients co-infected with HBV and HIV. Although the exact position of entecavir relative to other agents, such as tenofovir disoproxil fumarate and adefovir dipivoxil, for the treatment of chronic HBV infection remains to be fully determined, an important aspect in this positioning is the emergence of drug resistance. Hence, entecavir therapy provides a valuable first-line option in nucleoside-naive patients with chronic HBV infection and is a useful alternative in lamivudine-refractory patients.