Occult Hepatitis B virus (o-HBV) infection has been reported in HB surface antigen (HBsAg)-negative liver donors whose risk of transmitting HBV justifies a specific prophylaxis in liver recipients. The clinical significance of o-HBV infection in HBsAg-negative recipients and their need for prophylaxis is unknown. Liver samples collected during surgery from 23 HBsAg-negative patients (9 liver donors and 14 recipients) and 20 HBsAg-positive recipients (controls) were studied by polymerase chain reaction with an independent set of primers mapping the core and surface HBV genes. Intrahepatic HBV DNA was detected as core and surface genes in all the HBsAg-positive recipients, in none of the HBsAg-negative donors and in 9/14 (64%) of the HBsAg-negative recipients (2 HCV negative, 7 HCV positive). The intrahepatic amount of HBV was significantly lower in HBsAg-negative than in HBsAg-positive livers (median values 1.36 Log10/μg DNA vs. 3.66 Logs, p<0.0001, core gene, and 1.13 vs. 6.21 Logs p<0.0001, surface gene). No HBV DNA was detected in plasma from o-HBV recipients; one of them tested positive in lymphocytes. No correlation was found between o-HBV and serologic markers of previous HBV exposure, response to vaccination, acute rejection, hepatitis D and G virus-infections. None of o-HBV carriers experienced a de novo hepatitis B after transplantation (median follow-up: 477 days). Occult HBV is frequent in HBsAg-negative liver recipients. It is not associated with increased episodes of acute rejection, coinfection with hepatotropic viruses, different responses to HBV vaccination, or the development of de-novo hepatitis B. In o-HBV infection a particular virus-host interaction can explain the low intrahepatic HBV content and the lack of extrahepatic HBV replication, thus justifying the low risk of hepatitis B reactivation, in absence of specific prophylaxis, once the recipient liver is removed. (Liver Transpl 2004;10:356–362.)