We found that SP clusterin markedly inhibits the attachment of HIV-1 BAL (5 ng p24 antigen) to DC in a dose-dependent mode (1–40 μg/ml), being the percentage of inhibition of 54 ± 11(n = 6, p < 0.05) when used at a concentration of 15 μg/ml. Similar levels of inhibition were observed using blocking antibodies directed to DC-SIGN. In transmission experiments DC were cultured with HIV-1 BaL (5 ng p24Ag) in the presence of clusterin (20 μg/ml), washed and cultured with activated peripheral blood mononuclear cells (PBMCs). Clusterin markedly prevented virus transmission to DC: % inhibition = 59 ± 17, n = 5, p < 0.05). Experiments performed with THP-1-DC-SIGN+ cells showed that clusterin, at a concentration of 15 ug/ml, almost completely inhibited both, the attachment of HIV (% inhibition < 87%, n = 5) and the ability of THP-1-DC-SIGN+ cells to transmit the virus to activated PBMCs (% inhibition < 82%, n = 4).