Adverse drug reactions (ADR) are an important medical problem. The aim of this study is to investigate the clinical characteristics of children with ADR and to assess the tolerability of alternative drugs in children (under 16 yrs of age) with a history of ADR. We studied 278 children (132 males and 146 females). Patients were studied by recording personal history and performing in vivo skin testing, in vitro laboratory tests and challenge tests. Patients who had experienced mild adverse reactions underwent challenge tests without any premedication; patients with a clinical history of moderate reactions, received a premedication with sodium chromolyn 30 min before the oral challenge; patients with a clinical history of severe reactions or undergoing parenteral challenges, were given an antihistamine 30 minutes before. A total of 660 adverse events were reported with 126 different drugs involved. Antimicrobial agents were the most involved drugs (51.7%). Non-steroidal anti-inflammatory drugs were involved in 22.7% of episodes. The most reported symptoms were cutaneous. Allergy testing was negative in 272 patients. A diagnosis of drug allergy was reported for 6 patients. A total of 669 challenge tests were performed. 639 were negative at first attempt while 22 were positive. Eight were repeated using a different premedication and resulted negative. Hypersensitivity drug reactions in children are mainly non-allergic. A premedication with sodium cromolyn or with oral H1-antihistamines may be useful in preventing ADR.