INTRODUCTION: Inhibitor development against factor VIII (FVIII) is the most common complication of hemophilia A replacement therapy. One of the variables considered to influence inhibitor development is the ABO blood group. Patients with blood group O have, on average, a 30%-40% lower endogenous von Willebrand factor (VWF) concentration. It has been postulated that VWF levels influence inhibitor development. The objective of this study was to investigate the inhibitor risk in patients with severe hemophilia A comparing those with blood group O with those with non-O blood groups. METHODS: The study population consisted of children with severe hemophilia A, born between 2000 and 2020, who reached 50 FVIII exposure days in the PedNet registry. Inhibitors were considered to be clinically relevant when at least two consecutive measurements were tested positive. RESULTS: Routine testing of blood groups varied between centres: Out of 1172 patients with severe hemophilia A, blood group status was known in 759 patients (65.8%). The relative risk of inhibitor development for blood group O in comparison to non-O was 1.04 (95% CI: 0.7-1.7). CONCLUSION: In the PedNet cohort, blood group O did not increase the risk of inhibitors in previously untreated children with severe hemophilia A. TRIAL REGISTRATION: PedNet Registry; clinicaltrials.gov identifier: NCT02979119.