A retrospective study of the natural history of factor VIII inhibitors in haemophilia A patients experienced in a single comprehensive haemophilia centre over three decades is reported. 431 haemophilia A patients of all severities have been followed-up for a total of 5626 patient-years. The frequency of inhibitors was 10% in the severe haemophilia A patients and 37% occurred in children <10 years. The majority of the patients received several products before developing the inhibitors. 59% of patients had <50 exposure days and 48% were high responders (>5 BU). An 8-year (1987-95) inhibitor-free period was seen during which all previously untreated patients were treated with an intermediate-purity factor VIII concentrate. A moderate haemophiliac with a misense mutation that has not been described in association with inhibitor is reported. Six HIV-positive patients preserved their antibody response to factor VIII even at the advanced stage of their disease.