Icatibant, a bradykinin‐2 receptor antagonist, is administered by subcutaneous injection for the treatment of attacks of type I and type II hereditary angioedema. Following injection, patients feel transient pain followed by a short‐lived wheal and flare response at the injection site. We hypothesized that the icatibant‐induced wheal and flare response follows histamine release from activated skin mast cells and would therefore be reduced by an H₁‐antihistamine. Intradermal injection of 100 μl of 100 μg/ml histamine and 10 mg/ml icatibant into the forearms of health volunteers caused wheal and flare responses of a similar magnitude which were reduced by cetirizine pretreatment by 49% and 41% (histamine) and 35% and 41% (icatibant). Studies in vitro showed that icatibant at 1 × 10⁻⁴ and 1 × 10⁻⁵ m caused significant (P < 0.05) histamine release from isolated human cutaneous mast cells. In conclusion, icatibant induces histamine‐mediated wheal and flare responses that may be reduced in severity by prophylactic administration of an H₁‐antihistamine.