Background: Medial vascular calcification is a crucial risk factor for cardiovascular events and mortality in patients suffering from chronic kidney disease (CKD). This calcification develops as part of an active process mediated mainly by vascular smooth muscle cells (VSMCs), which are able to transdifferentiate into an osteo-/chondrogenic phenotype. The regulation of this transdifferentiation comprises complex intracellular signaling pathways and is related with inflammatory processes. Histamine levels are elevated in CKD and histamine may promote vascular inflammation. Thus, the present study explored the possible effects of histamine in vascular calcification. Methods: For this purpose, primary human aortic smooth muscle cells (HAoSMCs) were treated with histamine in the presence or absence of fexofenadine, an H1 histamine receptor antagonist. The mRNA expression was determined by quantitative RT-PCR and the protein abundance by Western blotting. Results: Histamine induced in a dose-dependent manner osteo-/chondrogenic transdifferentiation of HAoSMCs, as shown by up-regulation of the mRNA expression of osteogenic transcription factors MSX2 and CBFA1 and of osteogenic enzyme alkaline phosphatase (ALPL). The H1 receptor was the main histamine receptor expressed in HAoSMCs whereas the expression of H2, H3 and H4 receptors was low. Additional treatment with the H1 receptor antagonist fexofenadine suppressed the histamine-induced MSX2, CBFA1 and ALPL mRNA expression in HAoSMCs. These effects were paralleled by increased phosphorylation of p38 MAPK and SAPK/JNK MAPK in histamine treated HAoSMCs, effects again abolished by addition of fexofenadine. Histamine treatment did not significantly affect the phosphorylation of ERK1/2 MAPK. Moreover, TNFα and IL6 mRNA expression was up-regulated by histamine in HAoSMCs, effects blunted in the presence of fexofenadine. Conclusions: Histamine promotes osteo-/chondrogenic transdifferentiation of VSMCs, an effect mediated at least in large part through the H1 histamine receptor. These effects involve activation of the p38 and SAPK/JNK MAPK signaling pathways. Thus, histamine may participate in the progression of vascular calcification during CKD.