Allergic reactions associated to the use of macrolides are uncommon; in particular only two cases of anaphylaxis with erithromycin and clarithromycin have been reported to date. The aim of this study was to investigate macrolide-induced anaphylaxis. Between December 2007 and December 2011, 136 consecutive children were referred to the Allergy Unit of A. Meyer Children's Hospital because of a past history of reactions to macrolides. Allergy work-ups were carried out according to the European Network for Drug Allergy protocol. Anaphylaxis was diagnosed according to the clinical criteria proposed by Sampson et al. and graded according to Brown SGA et al. Sixty-six out of 136 patients completed the allergologic work-up and among them we investigated three cases of anaphylaxis due to azithromycin which included one child with anaphylaxis to both clarithromycin and azithromycin. In two of the children with anaphylaxis, the diagnosis was only confirmed with the skin prick test, the third was positive to the Intradermal Test. The azithromycin allergy shows a surprisingly high sensitivity to the in-vivo tests. Moreover, this study shows that cross-reactivity may occur between different macrolidic molecules; it has even been suggested that macrolide allergies are unlikely to be class allergies.