The glycan shield comprised of multiple carbohydrate chains on the human immunodeficiency virus (HIV) envelope glycoprotein gp120 helps the virus to evade neutralizing antibodies. The present study describes a novel method for increasing immunogenicity of gp120 vaccine by enzymatic replacement of sialic acid on these carbohydrate chains with Gal␣1-3Gal1-4GlcNAc-R (␣-gal) epitopes. These epitopes are ligands for the natural anti-Gal antibody constituting ϳ1% of immunoglobulin G in humans. We hypothesize that vaccination with gp120 expressing ␣-gal epitopes (gp120 ␣gal ) results in in vivo formation of immune complexes with anti-Gal, which targets vaccines for effective uptake by antigen-presenting cells (APC), due to interaction between the Fc portion of the antibody and Fc␥ receptors on APC. This in turn results in effective transport of the vaccine to lymph nodes and effective processing and presentation of gp120 immunogenic peptides by APC for eliciting a strong anti-gp120 immune response. This hypothesis was tested in ␣-1,3-galactosyltransferase knockout mice, which produce anti-Gal. Mice immunized with gp120 ␣gal produced anti-gp120 antibodies in titers that were >100-fold higher than those measured in mice immunized with comparable amounts of gp120 and effectively neutralized HIV. T-cell response, measured by ELISPOT, was much higher in mice immunized with gp120 ␣gal than in mice immunized with gp120. It is suggested that gp120 ␣gal can serve as a platform for anti-Gal-mediated targeting of additional vaccinating HIV proteins fused to gp120 ␣gal , thereby creating effective prophylactic vaccines.