Dengue virus (DV) is a single-stranded, enveloped RNA virus that infects human dendritic cells (DCs) primarily at the immature stage. This study shows that all four serotypes of DV use DC-SIGN (CD209), a C-type lectin, to infect DCs. Transfection of DC-SIGN or its homologue L-SIGN into THP-1 cells makes them susceptible to DV infection, while anti-DC-SIGN antibodies block infection. Viruses produced by DCs are infectious for DC-SIGN and L-SIGN-bearing cells, indicating DC-SIGN as a potential target for therapies against DV. DC-SIGN is expressed on a subset of DCs and certain endothelial cells. It allows immature DCs to capture and replicate DV after transmission from the mosquito vector. DC-SIGN mediates DV entry into DCs, enabling productive infection and virus transmission. Anti-DC-SIGN antibodies significantly block DV infection in DCs and THP-1 cells. The cytoplasmic domain of DC-SIGN enhances but is not essential for infection. DC-SIGN also facilitates the spread of infection from DCs to other cells. The study highlights DC-SIGN as a key receptor for DV infection and suggests it as a potential target for therapeutic interventions. The findings have implications for vaccine design and the development of therapies to prevent DV infection.Dengue virus (DV) is a single-stranded, enveloped RNA virus that infects human dendritic cells (DCs) primarily at the immature stage. This study shows that all four serotypes of DV use DC-SIGN (CD209), a C-type lectin, to infect DCs. Transfection of DC-SIGN or its homologue L-SIGN into THP-1 cells makes them susceptible to DV infection, while anti-DC-SIGN antibodies block infection. Viruses produced by DCs are infectious for DC-SIGN and L-SIGN-bearing cells, indicating DC-SIGN as a potential target for therapies against DV. DC-SIGN is expressed on a subset of DCs and certain endothelial cells. It allows immature DCs to capture and replicate DV after transmission from the mosquito vector. DC-SIGN mediates DV entry into DCs, enabling productive infection and virus transmission. Anti-DC-SIGN antibodies significantly block DV infection in DCs and THP-1 cells. The cytoplasmic domain of DC-SIGN enhances but is not essential for infection. DC-SIGN also facilitates the spread of infection from DCs to other cells. The study highlights DC-SIGN as a key receptor for DV infection and suggests it as a potential target for therapeutic interventions. The findings have implications for vaccine design and the development of therapies to prevent DV infection.