Whereas there has been recent interest in interactions between dendritic cells and pathogenic viruses, the role of dendritic cells in the initiation of protective immunity to such organisms has not been elucidated. The aim of this study was to examine whether a resident dendritic cell population in the skin, Langerhans cells, respond to cutaneous viral infections which are effectively cleared by the immune system. We therefore characterized the ability of Langerhans cells to migrate to local draining lymph nodes following infection with the arthropod-borne viruses, West Nile virus or Semliki Forest virus. The data show that major histocompatibility complex class II+/NLDC145+/E-cadherin+ Langerhans cell numbers are increased in the draining lymph nodes of infected mice and this increase is accompanied by a concomitant decrease in the Langerhans cell density in the epidermis. Langerhans cell migration is associated with an accumulation of leukocytes in the lymph node, which is one of the earliest events in the initiation of an immune response. Both the migratory response and the draining lymph node leukocyte accumulation were abrogated if ultraviolet-inactivated instead of live viruses were used, suggesting the activation and subsequent migration of Langerhans cells requires a live, replicating antigen. Our findings are likely to have wider implications for the development of epidermally delivered vaccines and suggest that mobilization of dendritic cells may be involved in the development of immune responses to arthropod-borne viruses.