CD40 antigen, expressed on many cell types is involved in cell-cell interactions, with activated T cells expressing the CD40 ligand. In the skin, keratinocytes express CD40 which may play a role in amplifying inflammatory responses. We investigated the expression of this antigen in a series of epidermal tumors in correlation with T cell infiltrates. Our results indicate a-down-regulation or a drastic loss of CD40 antigen by tumor cells from basal cell carcinoma and squamous cell carcinoma and a moderate to discrete CD40 reactivity of keratinocyte from proliferative layers of benign viral-induced lesions. Endothelial cells, most infiltrating cells and a subpopulation of intraepidermal dendritic cells strongly expressed CD40, mainly in benign lesions, in which T cell-keratinocyte interactions may be observed, and were restricted to epithelial cells expressing CD40. The lack of CD40 expression by tumor cells might account for tumor escape mechanism from activated T cells expressing the CD40 ligand.