Antiviral prophylaxis with hepatitis B immunoglobulin (HBIg) plus lamivudine reduces the risk of hepatitis B virus (HBV) recurrence after HBV-related liver transplant (LT). However, HBIg is expensive, and lamivudine therapy is limited by drug resistance. This study assessed a pilot study of entecavir plus low-dose, on-demand HBIg in preventing HBV recurrence after LT. Between 2006 and May 2011, approximately 145 patients undergoing HBV-related LT and receiving entecavir plus low-dose, on-demand HBIg were enrolled and followed for a median of 36 months. A historical control group of 171 patients undergoing HBV-related LT between 1998 and 2010 and receiving lamivudine plus HBIg were followed for a median of 77 months. The primary end point was the proportion of patients with recurrent HBsAg-positivity. In the entecavir cohort, 2 (1.37%) of 145 patients experienced HBV recurrence, none of which had evidence of viral resistance. In the lamivudine cohort, 11 (6.4%) of 171 cases of HBV recurrence were observed, 5 of which were associated with lamivudine resistance. The cumulative probabilities of HBV recurrence were significantly different between both cohorts (P=0.055). HBsAg recurrence was associated with lower overall survival (P<0.001), even in patients with undetectable HBV DNA. Using pooled data from both cohorts, predictors of HBV recurrence were nucleoside selection, pre-LT hepatocellular carcinoma, post-LT low anti-HBs, male sex, and HBsAg-positivity in the explant liver tissue. Entecavir plus low-dose, on-demand HBIg resulted in a low rate of HBV recurrence without evidence of resistance development and provided an effective and cost-saving strategy for patients having HBV-related LT.