HIV infection is pandemic in humans and is responsible for millions of deaths every year. The discovery of new cellular targets that can be used to prevent the infection process represents a new opportunity for developing more effective antiviral drugs. In this context, dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), a lectin expressed at the surface of immature dendritic cells and involved in the initial stages of HIV infection, is a promising therapeutic target. Herein we show the ability of a new tetravalent dendron containing four copies of a linear trimannoside mimic to inhibit the trans HIV infection process of CD4+ T lymphocytes at low micromolar range. This compound presents a high solubility in physiological media, a neglectable cytotoxicity, and a long-lasting effect and is based on carbohydrate-mimic units. Notably, the HIV antiviral activity is independent of viral tropism (X4 or R5). The formulation of this compound as a gel could allow its use as topical microbicide.