Multinucleate cell angiohistiocytoma (MCAH) is a putative reactive skin lesion, which has been reported mostly in adult female patients, and hormones have been recently suggested as a factor influencing its development. To test this hypothesis, monoclonal anti-estrogen receptor (ER) a, anti-progesterone receptor (PR), anti-Factor XIIIa, and polyclonal anti-vascular endothelial growth factor (VEGF) antibodies were applied by immunohistochemistry on a series of 21 MCAHs and, compared to 10 cases of dermatofibroma (DF) and 5 cases of chronic dermatitis presenting multinucleate cells. On normal skin surrounding the lesions and in cases of DF and chronic dermatitis, ERa was expressed in few undifferentiated and differentiated sebocytes, in few cells of anagen follicles and perifollicular mesenchymal cells, and in scattered dermal fibrocytes. In MCAHs, ERa was strongly expressed in interstitial spindle cells, spindle cells surrounding the characteristic vascular component of the lesion, and rare multinucleate cells. PR expression was restricted to sparse spindle cells and few sebocytes, whereas Factor XIIIa stained spindle cells in the dermis of normal and inflamed skin and in both MCAH and DF, and VEGF staining resulted completely negative. ERα, PR, and VEGF have been reported as poorly expressed in normal skin. In the present study, expression of ERα resulted upregulated in cases of MCAH, particularly in spindle cells, compared with that in DF cases. These findings underline the pathogenetic difference between MCAH and DF and also corroborate the suggested hypothesis of a role played by hormones, mainly ERα, in the development of this lesion. These observations could open a new strategy in the treatment of MCAH by antiestrogen therapy.