CD14+ dendritic cells (DCs) present in the dermis of human skin represent a large subset of dermal DCs (dDCs) that are considered macrophage-like cells with poor antigen (cross)-presenting capacity and limited migratory potential to the lymph nodes. CD14+ dDC highly express DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), a receptor containing potent endocytic capacity, facilitating intracellular routing of antigens to major histocompatibility complex I and II (MHC-I andII) loading compartments for the presentation to antigen-specific CD8+ and CD4+ T cells. Here we show using a human skin explant model that the in situ targeting of antigens to DC-SIGN using glycan-modified liposomes enhances the antigen-presenting capacity of CD14+ dDCs. Intradermal vaccination of liposomes modified with the DC-SIGN-targeting glycan LewisX, containing melanoma antigens (MART-1 or Gp100), accumulated in CD14+ dDCs and resulted in enhanced Gp100- or MART-1-specific CD8+ T-cell responses. Simultaneous intradermal injection of the cytokines GM-CSF and IL-4 as adjuvant enhanced the migration of the skin DCs and increased the expression of DC-SIGN on the CD14+ and CD1a+ dDCs. These data demonstrate that human CD14+ dDCs exhibit potent cross-presenting capacity when targeted in situ through DC-SIGN.