The study identifies DC-SIGN (CD209) and L-SIGN as key mediators of dengue virus (DV) infection in human dendritic cells (DCs). All four serotypes of DV use DC-SIGN to infect immature DCs, which are preferentially infected compared to mature DCs. Transfection of THP-1 cells with DC-SIGN or L-SIGN renders them susceptible to DV infection, which is blocked by anti-DC-SIGN antibodies but not by other antibodies. The produced viruses are infectious for DC-SIGN+ and L-SIGN+ cells, suggesting that DC-SIGN may be a new target for therapeutic interventions against DV infection. The findings highlight the importance of DC-SIGN in DV entry and provide insights into potential strategies for preventing or treating DV infections.The study identifies DC-SIGN (CD209) and L-SIGN as key mediators of dengue virus (DV) infection in human dendritic cells (DCs). All four serotypes of DV use DC-SIGN to infect immature DCs, which are preferentially infected compared to mature DCs. Transfection of THP-1 cells with DC-SIGN or L-SIGN renders them susceptible to DV infection, which is blocked by anti-DC-SIGN antibodies but not by other antibodies. The produced viruses are infectious for DC-SIGN+ and L-SIGN+ cells, suggesting that DC-SIGN may be a new target for therapeutic interventions against DV infection. The findings highlight the importance of DC-SIGN in DV entry and provide insights into potential strategies for preventing or treating DV infections.