Human immunodeficiency virus (HIV) binds to the surface of CD4 positive lymphocytes and monocyte/macrophages via a high affinity interaction between CD4 and the HIV envelope glycoprotein gp120 and is internalized by fusion of the virus and the cell membrane. The third variable (V3) domain of gp120 also plays a central role in the fusion and viral entry process. Reagents that neutralize HIV by binding to the CD4 binding domain or V3 domain of gp120 have been proposed as therapeutics in the post-HIV exposure and perinatal setting. However, the neutralization potency of these proposed reagents, sCD4, V3 directed and CD4 binding domain directed monoclonal antibodies (MAbs), is intermediate at best and may be of limited use in a clinical setting. We have demonstrated that the combination of reagents to these two primary targets for neutralization resulted in synergy with 10- to 1000-fold increase in virus neutralization. The addition of these combined reagents a second time 3 and 5 days postinfection resulted in an additional 10-fold increase in neutralization suggesting a block in HIV spread from cell to cell. These data suggest that a combination of CD4 binding domain reagents and V3 antibody infused at intervals may significantly reduce the viral load in AIDS patients.