Patients with chronic hepatitis B virus (HBV) infection have a defective HBV-specific immune response, and the spontaneous development of antibody against hepatitis B surface antigen (anti-HBs) after liver transplantation has not been observed. We report the spontaneous production of anti-HBs in 21 of 50 (42%) patients receiving lamivudine monoprophylaxis after liver transplantation. Seroconversion to anti-HBs status (>10 mIU/mL) was found at a median of 8 days (range, 1 to 43 days) after transplantation. In each case, serial serum samples showed a >100% increase in antibody titer as compared with that of day 7 after transplantation in the absence of any blood product transfusion. The anti-HBs titer increased to a maximum within 3 months, and the peak titer was <100 mIU/mL in 10 patients, 100 to 1000 mIU/mL in 5 patients, and >1,000 mIU/mL in 6 patients. In 12 patients, anti-HBs disappeared from serum at a median of 201 days (range, 24 to 414 days), whereas the other 9 patients remained positive for anti-HBs at a median of 221 days (range, 94 to 1,025 days) after transplantation. Patients in whom anti-HBs in serum developed had a more rapid clearance of serum hepatitis B surface antigen (HBsAg) (log rank test, P = .011). Using logistic regression analysis, the only predictor of anti-HBs production was an HBV-immune donor (odds ratio, 18.9; 95% confidence interval, 3.2 to 112.4; P = .001). In conclusion, patients who undergo liver transplantation for chronic hepatitis B using lamivudine prophylaxis may develop anti-HBs spontaneously. The antibody is likely to be of donor origin, suggesting the possibility of adoptive immunity transfer through a liver graft.