Histamine is an important mediator released from activated mast cells provoked by allergen and has a substantial role in the pathophysiology of asthma. However, several lines of evidence indicate that histamine could also have important functions in the regulation of basic cell biological processes. We have used histidine decarboxylase gene‐targeted (HDC‐KO) mice, lacking histamine, to investigate the effect of histamine deficiency in an animal model of asthma. Our previous investigations revealed that HDC‐KO mice had fewer mast cells with reduced granular content and defective degranulation characteristics. Ovalbumin (OVA)‐sensitized and challenged HDC‐KO mice had significantly reduced airway hyper‐responsiveness, lung inflammation, bronchoalveolar lavage eosinophilia, and OVA‐specific IgE compared with congenic wild‐type littermates treated in the same way. Comparing the expression profiles of cytokines, the levels of IL‐1α, IL‐1β, IL‐4, IL‐5, IL‐6 and IFN‐γ were significantly lower in the HDC‐KO mice in asthmatic late phase, indicating a significantly altered immune response to OVA provocation and challenge. Evaluation of chemokine gene expression revealed that OVA treatment caused elevation of both T_h1‐ and T_h2‐type chemokines in wild‐type mice, while the chemokine expression was polarized toward a T_h1 response in HDC‐KO mice. According to our results we can suggest that the possible causes of the reduced asthma symptoms in the HDC‐KO mice may be the imperfect mast and eosinophil cell system, and an altered immune response to OVA provocation and challenge.