Vitamin K prophylaxis in infancy aims to prevent life-threatening vitamin K deficiency bleeding (VKDB). The Dutch prophylactic oral daily regimen was increased sixfold from 25 to 150 μg because of a high failure rate. To evaluate the efficacy of this new regimen, incidences of intracranial VKDB under both regimens were compared using both general and targeted surveillance. Late VKDB in the general pediatric population was identified by the Netherlands Pediatric Surveillance Unit, between 1 October 2014 and 31 December 2016. Additionally, infants with intracranial vitamin K deficiency bleeding were identified using the Dutch Pediatric Intensive Care Evaluation registry. The incidence of intracranial VKDB as assessed by general and targeted surveillance decreased from 1.6 per 100,000 (95% CI, 0.4–5.1) to 1.3 per 100,000 (95% CI, 0.5–3.2) and from 3.1 per 100,000 live births (95% CI, 1.9–5.0) to 1.2 per 100,000 live births (95% CI, 0.6–2.3), respectively. Median time between consecutive cases in the latter increased from 24 to 154 days (p < 0.001). Conclusion: A sixfold increase in oral vitamin K prophylaxis was associated with a surprisingly modest reduction in the incidence of intracranial VKDB, indicating that factors other than the dose need addressing to improve efficacy.What is Known:• The efficacy of intramuscular vitamin K prophylaxis is threatened by an increasing number of parents opting out.• Oral prophylaxis represents an attractive and less invasive alternative but is inferior, especially in infants with malabsorption of vitamin K due to cholestasis.What is New:• Increasing the daily oral dose of vitamin K sixfold had a surprisingly modest effect on the incidence of late vitamin K deficiency bleeding.• This finding indicates that factors other than the dose must play an important role.