To evaluate the role of maternal hepatitis B virus (HBV) DNA levels in perinatal infection, two nested case-control studies were done within a cohort of 773 hepatitis B surface antigen (HBsAg)-positive Taiwanese women and their infants. As serum HBV DNA levels increased from < 0.005 to > or = 1.4 ng/mL among the hepatitis B e antigen (HBeAg)-positive mothers, the odds ratio (OR) for having a persistently infected infant increased from 1.0 to 147.0 (P for trend < .001). Among HBeAg-negative mothers, the OR for having a persistently infected infant was 19.2 (95% confidence interval, 2.3-176.6) in mothers with high versus low levels of serum HBV DNA. A logistic regression analysis identified maternal HBV DNA to be a stronger independent predictor of persistent infection than HBeAg status. Thus, perinatal exposure to high levels of maternal HBV DNA is the most important determinant of infection outcome in the infant.