The role of Langerhans cells (LC) in the initiation of an immune response to a viral infection remains unclear. In vivo epidermal infection with the arboviruses West Nile virus and Semliki Forest virus significantly increased the expression of major histocompatibility complex class II antigens, CD54, and CD80 on LC. Thus, during an epidermally acquired viral infection, local LC appear to mature to a phenotype approximating that of lymphoid dendritic cells. This change may be important in the activation of naïve T cells and the subsequent clearance of viral infection.