This case–control study investigated the interactions between genetic and environmental factors and inhibitor development in 108 children with haemophilia A exclusively treated with recombinant factor VIII (FVIII). Sixty patients with inhibitors were compared with 48 inhibitor-free controls. Family history of inhibitors and null mutations in the FVIII gene were more prevalent in cases than in controls (20% vs. 2%, P = 0·001 and 83% vs. 64%, P = 0·04, respectively). On the other hand, there was no difference between cases and controls for such putative risk factors of inhibitor development as amniocentesis/villocentesis, premature/caesarean birth, breast-feeding, treatment during infections/vaccinations, surgical procedures and central nervous system bleeding. A trend was found for an increased risk of inhibitor development in children first treated at a young age (<11 months); however, this was not confirmed after adjusting for genetic factors. The implementation of prophylaxis was evaluated as a putative risk factor in a subgroup of 25 cases: seven who started prophylaxis prior to inhibitor development and 18 potentially eligible for prophylaxis because they were inhibitor-free up to the age of 35 months (i.e. the upper limit of the age range at prophylaxis onset in cases and the median age at prophylaxis onset in controls). Patients who started prophylaxis had a lower inhibitor risk than those treated on demand (adjusted odds ratio 0·2, 95% confidence interval 0·06–0·9). The protective effect on inhibitor development shown by prophylaxis may represent an additional advantage prompting its use in haemophilic children.