The entry of the human immunodeficiency virus type 1 (HIV-1) into target cells requires the interaction of viral envelope glycoprotein, gp120, with the human CD4 glycoprotein and a chemokine receptor, usually CCR5 or CXCR4. The natural ligand for CXCR4 is the chemokine SDF-1 that inhibits entry and replication of X4 HIV-1 strains. SDF-1 is produced in two forms, SDF-1α (68 residues) and SDF-1β (72 residues); the difference between them lies in the additional four C-terminal amino acids in the SDF-1β sequence. Despite the relevance of the N-terminal site in determining the SDF anti HIV-1 activity, SDF-1β has a stronger activity than SDF-1α. Here we demonstrate that a synthetic peptide mapped on the C-terminus of SDF-1β presents inhibitory activity, whereas an analogue reproducing the C-terminal trait of SDF-1α does not show any activity. The opposite biological effect of the two peptides correlates with the type of interaction they each have with heparin and chondroitin sulfate.