Among the different subsets of dendritic cells (DC) described in humans and mice, epidermal Langerhans cells and dermal DCs represent the only DC populations resident in normal skin. In this study we describe a population of CD4+ CD3− plasmacytoid DC (pDC)-like cells that accumulate in the dermis and spleens of mice topically treated with imiquimod, a low mw immune response modifier with potent antiviral and antitumor activities. These CD4+ CD3− cells coexpress GR-1, B220, MHC class II, and, to a lesser extent, CD11c and display the phenotypic features of pDCs described in lymphoid organs. The accumulation of pDC-like cells after imiquimod treatment was detected not only in normal skin, but also in intradermally induced melanomas. Imiquimod treatment leads either to complete regression or to a significant reduction of the tumors. The number of pDCs correlates well with the clinical response of the tumors to the drug, suggesting that the antitumor effects of imiquimod could be mediated at least in part by the recruitment of pDC-like cells to the skin. Therefore, strategies aimed at activating and directing these cells into neoplastic tissues may be a promising and novel approach for the immunotherapy of various types of cancer.