De novo hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) is commonly believed to be a relatively benign condition, in contrast to post-OLT infection recurrence, considered a very aggressive complication. We reviewed the charts of 569 non-HBV-related OLTs performed at our institution and identified 19 patients (3%) with de novo HBV infection (appearance of hepatitis B surface antigen [HBsAg] after OLT). After a median follow-up of 25 months beyond the detection of HBsAg, 12 patients (63%) had developed serious HBV-related graft damage (cirrhosis in 6 patients, bridging chronic hepatitis in 4 patients, and fulminant hepatitis in 2 patients); 7 patients (37%) had lost their grafts; and 4 patients (21%) had died. All graft losses and deaths were related to de novo HBV infection. Similar rates of severe graft damage (62%), graft loss (38%), and death (33%) related to HBV infection were found in a concomitant series of 21 patients with recurrent HBV infection after OLT. Responses to antiviral therapy (interferon or lamivudine) were also similar in the 2 groups of patients. In 12 patients with de novo HBV infection, evidence of past HBV infection (positive serum antibody to hepatitis B core antigen and/or serum or liver tissue HBV DNA) were detected in the donor (7 patients) or recipient (5 patients). No differences were observed in the clinical course after stratification according to the attributed origin of de novo HBV infection. We conclude that de novo HBV infection after OLT is associated with high rates of morbidity and mortality, similar to those described for post-OLT HBV infection recurrence.