The nocebo effect is the onset of untoward reactions following the administration of an indifferent substance. The oral challenge with alternative drugs plays a central role in the management of drug allergy and the use of inert substances is part of this procedure. We evaluated the occurrence and clinical characteristics of nocebo effect in patients with adverse drug reactions. Six hundred patients, seen in three different centres (Genoa, Naples and Verona) with a history of reactions to drugs, underwent a blind oral challenge with the administration of an indifferent substance and active drugs. The administration of an inert substance provoked untoward reactions in 54 patients (27%) in Verona, 60 (30%) in Naples and 48 (24%) in Genoa. The overall occurrence of nocebo effect was 27%. The majority of reactions were subjective symptoms (itching, malaise, headache etc), perceived as troublesome by all subjects. The occurrence was significantly higher in women than in men. Our data, collected in a large population, confirm that the nocebo effect occurs frequently in clinical practice. In managing adverse drug reactions through oral challenge the nocebo effect is mandatory to recognize false positive responses.