OBJECTIVE: Newborns routinely receive vitamin K to prevent vitamin K deficiency bleeding. The efficacy of oral vitamin K administration may be compromised in infants with unrecognized cholestasis. We aimed to compare the risk of vitamin K deficiency bleeding under different prophylactic regimens in infants with biliary atresia. PATIENTS AND METHODS: From Dutch and Danish national biliary atresia registries, we retrieved infants who were either breastfed and received 1 mg of oral vitamin K at birth followed by 25 microg of daily oral vitamin K prophylaxis (Netherlands, 1991-2003), 2 mg of oral vitamin K at birth followed by 1 mg of weekly oral prophylaxis (Denmark, 1994 to May 2000), or 2 mg of intramuscular prophylaxis at birth (Denmark, June 2000-2005) or were fed by formula. We determined the absolute and relative risk of severe vitamin K deficiency and vitamin K deficiency bleeding on diagnosis in breastfed infants on each prophylactic regimen and in formula-fed infants. RESULTS: Vitamin K deficiency bleeding was noted in 25 of 30 of breastfed infants on 25 microg of daily oral prophylaxis, in 1 of 13 on 1 mg of weekly oral prophylaxis, in 1 of 10 receiving 2 mg of intramuscular prophylaxis at birth, and in 1 of 98 formula-fed infants (P < .001). The relative risk of a bleeding in breastfed compared with formula-fed infants was 77.5 for 25 microg of daily oral prophylaxis, 7.2 for 1 mg of weekly oral prophylaxis, and 9.3 for 2 mg of intramuscular prophylaxis at birth. CONCLUSIONS: A daily dose of 25 microg of vitamin K fails to prevent bleedings in apparently healthy infants with unrecognized cholestasis because of biliary atresia. One milligram of weekly oral prophylaxis offers significantly higher protection to these infants and is of similar efficacy as 2 mg of intramuscular prophylaxis at birth. Our data underline the fact that event analysis in specific populations at risk can help to evaluate and improve nationwide prophylactic regimens.