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Asthma is a chronic inflammatory disease that is associated with airway remodeling, including hyperplasia of airway epithelial cells and airway smooth muscle cells, and goblet cell differentiation. We wished to address the potential role of histamine, a key biogenic amine involved in allergic reactions, in airway remodeling through the epidermal growth factor receptor (EGFR) pathway. Here, we demonstrate that histamine releases 2 EGFR ligands, amphiregulin and heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), from airway epithelial cells. Amphiregulin and HB‐EGF were expressed in airway epithelium of patients with asthma. Histamine up‐regulated their mRNA expression (amphiregulin 3.2‐fold, P< 0.001; HB‐EGF 2.3‐fold, P<0.05) and triggered their release (amphiregulin EC₅₀ 0.50 μM, 31.2±2.7 pg/ml with 10 μM histamine, P<0.01; HB‐EGF EC₅₀ 0.54 μM, 78.5±1.8 pg/ml with 10 μM …