Context: The development of inhibitory antibodies against infused factor (F) VIII is a major complication of treatment of patients with severe hemophilia A.Objective: This study was set up to examine the effects of treatment-related factors on inhibitor development among previously untreated patients with severe hemophilia A.Design, setting and patients: In this multicenter cohort study, we combined individual patient data obtained from four recombinant FVIII product registration studies (Kogenate®, Kogenate Bayer®, Recombinate®, ReFacto®) that were performed between 1989 and 2001. From the databases we selected all 236 previously untreated patients with severe hemophilia A who were subsequently treated with FVIII on at least 50 days.Main outcome measures: Clinically relevant inhibitor development, defined as the occurrence of at least two positive inhibitor titers and a decreased recovery.Results: 67 patients (28%) developed clinically relevant inhibitors (44 high-titer) at a median of ten exposure days. Age at first exposure was not associated with inhibitor development. Peak treatment moments and surgical procedures were related to an increased inhibitor risk [adjusted relative risk 1.6 (95% confidence interval 1.0–2.6) and 2.7 (95% confidence interval 1.3–5.7), respectively]. A shorter duration between exposure days was associated with an increased risk of inhibitor development. There was a possible association between dosing of FVIII and inhibitor development, which largely disappeared after adjustment for confounding factors.Interpretation: These findings show that intensive treatment periods are associated with an increased risk of inhibitor development in previously untreated patients with severe hemophilia A. Our results do not support the notion that age at first exposure is associated with the risk of developing inhibitors.