To determine how the histaminergic system is implicated in vestibular compensation, we studied the changes in histidine decarboxylase (HDC; the enzyme synthesizing histamine) mRNA regulation in the tuberomammillary (TM) nuclei of cats killed 1 week, 3 weeks and 3 months after unilateral vestibular neurectomy (UVN). We also used one- and two-step bilateral vestibular neurectomized (BVN) cats to determine whether HDC mRNA regulation depended on the asymmetrical vestibular input received by the TM nuclei neurons. In addition, we analysed the HDC mRNA changes in the TM nuclei and the recovery of behavioural functions in UVN cats treated with thioperamide, a pure histaminergic drug. Finally, we quantified binding to histamine H3 receptors (H3Rs) in the medial vestibular nucleus (VN) by means of a histamine H3R agonist ([3H]N-alpha-methylhistamine) in order to further investigate the sites and mechanisms of action of histamine in this structure. This study shows that UVN increases HDC mRNA expression in the ipsilateral TM nucleus at 1 week. This increased expression persisted 3 weeks after UVN, and regained control values at 3 months. HDC mRNA expression was unchanged in the one-step BVN cats but showed mirror asymmetrical increases in the two-step BVN compared to the 1 week UVN cats. Three weeks' thioperamide treatment induced a bilateral HDC mRNA up-regulation in the UVN cats, which was higher than in the untreated UVN group. Binding to histamine H3Rs in the MVN showed a strong bilateral decrease after thioperamide treatment, while it was reduced ipsilaterally in the UVN cats. That such changes of the histaminergic system induced by vestibular lesion and treatment may play a functional role in vestibular compensation is strongly supported by the behavioural data. Indeed, spontaneous nystagmus, posture and locomotor balance were rapidly recovered in the UVN cats treated with thioperamide. These results demonstrate that changes in histamine levels are related to vestibular compensation.