Individuals coinfected with human immunodeficiency virus 1 (HIV-1) and hepatitis B virus (HBV) often receive treatment with an antiretroviral regimen including lamivudine. Lamivudine monotherapy for HBV may lead to drug-resistant mutations in a significant number of patients. The virological and biochemical responses of 8 patients coinfected with HBV/HIV-1 treated with both lamivudine and famciclovir were studied. Patients exhibiting HBV viral rebound at 1 year were analyzed for the emergence of HBV polymerase mutations. Only 1 patient had no prior exposure to lamivudine. Addition of famciclovir to the treatment regimen resulted in a median fall in HBV DNA level of 0.33 log(10) at 3 months and an overall rise in HBV DNA level of 3 log(10) at 12 months. The only patient in whom durable viral suppression and HBV e antigen seroconversion were noted began receiving lamivudine and famciclovir simultaneously. HBV polymerase gene sequencing identified resistance-associated mutations in 6 of 7 patients with viral rebound. Sequential nucleoside analogue therapy is unlikely to be successful in achieving long-term suppression of HBV replication, and combination therapy should be considered at treatment initiation.