BACKGROUND: Chronic hepatitis B infection carries considerable risk for the development of cirrhosis and hepatocellular carcinoma. Treatment options are increasing but are limited to interferon alfa-2b, pegylated interferon alfa-2a, lamivudine, adefovir dipivoxil, and entecavir. Entecavir, a nucleoside analog, is the newest oral antiviral approved in the United States for treatment of chronic hepatitis B. OBJECTIVE. To review the available data for entecavir regarding its pharmacology, pharmacokinetics, safety, efficacy, and clinical use. METHODS. A MEDLINE, EMBASE, and Cochrane search of the English-language literature from January 1997-May 2006 was performed. Preapproval studies provided by the manufacturer and abstracts from recent scientific meetings on infectious disease and hepatology were also reviewed. RESULTS. Three phase III clinical trials representing more than 1600 subjects established the superior efficacy and equivalent safety of entecavir compared with lamivudine for treating patients who are hepatitis B early antigen (HBeAg) positive, HBeAg negative, or refractory to lamivudine. Entecavir resistance has not occurred in nucleoside-naïve patients but may develop in those who already possess lamivudine resistance mutations. CONCLUSION. Trial results, along with previously published response rates for adefovir dipivoxil and interferon monotherapy, make entecavir the preferred first-line treatment option for patients with chronic hepatitis B who are nucleoside naïve, HBeAg positive or negative, and have compensated liver disease. Both entecavir and adefovir dipivoxil maintain activity against hepatitis B virus in patients with chronic hepatitis B who are refractory to lamivudine, and both agents are reasonable first-line treatment options. Longer trials involving nucleoside-naïve, lamivudine-refractory patients are needed to determine entecavir's optimal treatment duration, long-term safety, and durability of response, including rate of resistance.